KR20000076211A - Dolastatin-15 derivatives in combination with taxanes - Google Patents
Dolastatin-15 derivatives in combination with taxanes Download PDFInfo
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- KR20000076211A KR20000076211A KR1019997008305A KR19997008305A KR20000076211A KR 20000076211 A KR20000076211 A KR 20000076211A KR 1019997008305 A KR1019997008305 A KR 1019997008305A KR 19997008305 A KR19997008305 A KR 19997008305A KR 20000076211 A KR20000076211 A KR 20000076211A
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- 229940123237 Taxane Drugs 0.000 title claims abstract description 24
- LQKSHSFQQRCAFW-CCVNJFHASA-N [(2s)-1-[(2s)-2-benzyl-3-methoxy-5-oxo-2h-pyrrol-1-yl]-3-methyl-1-oxobutan-2-yl] (2s)-1-[(2s)-1-[(2s)-2-[[(2s)-2-[[(2s)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl]-methylamino]-3-methylbutanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carboxyl Chemical class C([C@@H]1N(C(=O)C=C1OC)C(=O)[C@@H](OC(=O)[C@H]1N(CCC1)C(=O)[C@H]1N(CCC1)C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C)C(C)C)C(C)C)C1=CC=CC=C1 LQKSHSFQQRCAFW-CCVNJFHASA-N 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 190
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims abstract description 81
- 238000000034 method Methods 0.000 claims abstract description 71
- 229930012538 Paclitaxel Natural products 0.000 claims abstract description 69
- 229960001592 paclitaxel Drugs 0.000 claims abstract description 69
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 55
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims abstract description 26
- 229940063683 taxotere Drugs 0.000 claims abstract description 26
- 201000011510 cancer Diseases 0.000 claims abstract description 20
- 239000000203 mixture Substances 0.000 claims abstract description 19
- -1 2,2-dimethylglycyl Chemical group 0.000 claims description 364
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 55
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 48
- 125000000217 alkyl group Chemical group 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 30
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 29
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- 125000000741 isoleucyl group Chemical group [H]N([H])C(C(C([H])([H])[H])C([H])([H])C([H])([H])[H])C(=O)O* 0.000 claims description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 23
- 238000011282 treatment Methods 0.000 claims description 23
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 15
- 241000124008 Mammalia Species 0.000 claims description 14
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- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 12
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- 238000002648 combination therapy Methods 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 10
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
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- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 6
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- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
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- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 3
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
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- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 210000004696 endometrium Anatomy 0.000 claims description 3
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims description 3
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
- 229950003188 isovaleryl diethylamide Drugs 0.000 claims description 3
- 125000000405 phenylalanyl group Chemical group 0.000 claims description 3
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000005493 quinolyl group Chemical group 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 125000004014 thioethyl group Chemical group [H]SC([H])([H])C([H])([H])* 0.000 claims description 3
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- 238000004519 manufacturing process Methods 0.000 claims 4
- 125000003670 adamantan-2-yl group Chemical group [H]C1([H])C(C2([H])[H])([H])C([H])([H])C3([H])C([*])([H])C1([H])C([H])([H])C2([H])C3([H])[H] 0.000 claims 2
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Abstract
본 발명은 대상의 암을 치료하기 위한 조성물 및 방법으로서, 본원에 규정된 화학식 (I)의 화합물을 파클리택셀, 택소테레 또는 개질된 택산 또는 택소이드 유사체와 조합시킴으로써 단일 화합물에 의해 달성되는 효과 보다 증강된 항암 효과를 제공하는 조성물 및 방법에 관한 것이다.The present invention provides a composition and method for treating cancer in a subject, the effect achieved by a single compound by combining a compound of formula (I) as defined herein with paclitaxel, taxotere or modified taxanes or taxoid analogs A composition and method for providing more enhanced anticancer effects.
Description
암은 다수의 잠재적으로 유효한 치료법이 이용가능한 질병이다. 그러나, 다양한 타입의 암의 만연 및 이것이 가질 수 있는 심각한 결과로 인해, 더욱 효과적인 치료법, 특히 현재 이용가능한 치료법 보다 적은 불리한 부작용을 갖는 치료법이 필요하게 되었다.Cancer is a disease in which many potentially effective therapies are available. However, the prevalence of various types of cancer and the serious consequences that it may have have resulted in the need for more effective therapies, especially those with fewer adverse side effects than currently available therapies.
발명의 요약Summary of the Invention
본 발명은 포유동물의 암을 치료하기에 유용한 약제 조성물에 관한 것이다. 본 발명의 약제 조성물은 2가지 화합물, 즉, 파클리택셀, 택소테레 또는 개질된 택산 또는 택소이드 유사체인 제 1 화합물 및 하기 화학식 (I)인 제 2 화합물을 포함한다:The present invention relates to pharmaceutical compositions useful for treating cancer in a mammal. Pharmaceutical compositions of the present invention comprise two compounds, a first compound that is paclitaxel, taxotere or a modified taxane or taxoid analog and a second compound of formula (I):
R1R2N-CHX-CO-A-B-D-(E)s-(F)t-(G)u-K (I)R 1 R 2 N-CHX-CO-ABD- (E) s- (F) t- (G) u -K (I)
화학식 (I)은 상세하게 후술된다. 화학식 (I)의 화합물의 몇몇 예가 본원에 구체적으로 제시되어 있다. 예를 들어, 화학식 (I)의 화합물은, R1및 R2가 각각 메틸 또는 에틸이고; X가 이소프로필, 2차 부틸 또는 3차 부틸이고; s가 1이고; t 및 u가 각각 0이고; A가 발릴, 이소루실 또는 2-3차부틸글리실이고; D가 디아졸리디닐카르보닐, 3,4-데히드로프롤릴 또는 프롤릴이고; E가 프롤릴, 티아졸리디닐-4-카르보닐, 호모프롤릴, 히드록시프롤릴 또는 3,4-데히드로프롤릴이고; K가 화학식 R5-N-R6을 갖는 치환된 아미노 부분이며, 여기서, R5는 수소 또는 C1-C4알콕시이고, R6은 1가 라디칼, 예를 들어 (1)- 또는 (2)-아다만틸; v가 1인 (CH2)v-페닐; α,α-디메틸벤질; C1-C12직쇄 또는 측쇄 히드록시알킬 그룹, 예를 들어 3-히드록시-1,1-디메틸프로필로서 또한 명명되는 C(CH3)2-CH2-CH2-OH; C3-C10시클로알킬 그룹, 예를 들어 비시클로[3.3.0]옥타-1-일, 1-메틸시클로펜틸 또는 1-메틸시클로헥실; 또는 C1-C12직쇄 또는 측쇄 알킬 그룹, 예를 들어Formula (I) is described later in detail. Some examples of compounds of formula (I) are specifically presented herein. For example, compounds of formula (I) are those wherein R 1 and R 2 are each methyl or ethyl; X is isopropyl, secondary butyl or tertiary butyl; s is 1; t and u are each 0; A is valeryl, isoleucyl or 2-3 tertiary butyl glycyl; D is diazolidinylcarbonyl, 3,4-dehydroprolyl or prolyl; E is prolyl, thiazolidinyl-4-carbonyl, homoprolyl, hydroxyprolyl or 3,4-dehydroprolyl; K is a substituted amino moiety having the formula R 5 -NR 6 , wherein R 5 is hydrogen or C 1 -C 4 alkoxy and R 6 is a monovalent radical such as (1)-or (2)- Adamantyl; (CH 2 ) v-phenyl, wherein v is 1; α, α-dimethylbenzyl; C (CH 3 ) 2 -CH 2 -CH 2 -OH, also named as C 1 -C 12 straight or branched hydroxyalkyl group, for example 3-hydroxy-1,1-dimethylpropyl; C 3 -C 10 cycloalkyl group, for example bicyclo [3.3.0] octa-1-yl, 1-methylcyclopentyl or 1-methylcyclohexyl; Or a C 1 -C 12 straight or branched alkyl group, for example
3차 부틸로서 또한 명명되는 C(CH3)3;C (CH 3 ) 3 , also named as tertiary butyl;
1,1-디메틸프로필로서 또한 명명되는;Also named as 1,1-dimethylpropyl ;
1-메틸-1-에틸프로필로서 또한 명명되는;Also named as 1-methyl-1-ethylpropyl ;
(S)- 또는 (R)-1-메틸-2,2-디메틸-프로필로서 또한 명명되는;Also named as (S)-or (R) -1-methyl-2,2-dimethyl-propyl ;
(S)- 또는 (R)-1-에틸-2-메틸프로필로서 또한 명명되는;Also named as (S)-or (R) -1-ethyl-2-methylpropyl ;
1-이소프로필-2-메틸-프로필로서 또한 명명되는; 또는Also named as 1-isopropyl-2-methyl-propyl ; or
1,1-디메틸-2-메틸프로필로서 또한 명명되는 -C(CH3)2-CH(CH3)2;-C (CH 3 ) 2 -CH (CH 3 ) 2 , also named as 1,1-dimethyl-2-methylpropyl;
이소프로필로서 또한 명명되는 -CH(CH3)2;-CH (CH 3 ) 2 , also named as isopropyl;
2차 부틸 [(S) 또는 (R)]로서 또한 명명되는 -CH(CH3)CH2CH3; 또는-CH (CH 3 ) CH 2 CH 3 , also referred to as secondary butyl [(S) or (R)]; or
-1,2-디메틸프로필로서 또한 명명되는 CH(CH3)CH(CH3)2인 화합물이다.CH (CH 3 ) CH (CH 3 ) 2 , which is also named as -1,2-dimethylpropyl.
각각의 화합물은 약제 조성물에서 유효량으로 존재한다. 약제 조성물은 각각의 타입의 화합물을 1종 이상 포함할 수 있다 (예를 들어, 1종 이상의 제 1 타입의 화합물, 예를 들어 파클리택셀 또는 파클리택셀 및 택소테레 및 1종 이상의 화학식 (I)의 화합물).Each compound is present in an effective amount in the pharmaceutical composition. The pharmaceutical composition may comprise one or more compounds of each type (eg, one or more compounds of the first type, such as paclitaxel or paclitaxel and taxotere and one or more formulas (I Compound).
또한, 본 발명은 본원에 기재된 약제 화합물을 사용하여 포유동물의 암을 치료하는 방법에 관한 것이다. 본 발명의 방법에 있어서, 2가지 화합물은 약제 조성물의 형태로 투여되거나, 원하는 효과를 갖기에 충분히 짧은 시간내에 제공되는 개별적/단독 화합물로서 투여된다.The present invention also relates to methods of treating cancer in mammals using the pharmaceutical compounds described herein. In the methods of the invention, the two compounds are administered in the form of pharmaceutical compositions or as individual / alone compounds provided in a time short enough to have the desired effect.
의외로, 본원에 기재된 파클리택셀, 택소테레 또는 개질된 택산 또는 택소이드 유사체와 본원에 기재된 화학식 (I)을 갖는 화합물이 조합되면, 증강되거나 치료적으로 상승된 생체내 항암 효과를 제공하는 것으로 발견되었다. 본 발명을 위해, 두 가지 약제는, 조합 치료에 의해, 약제가 최적 또는 최대 허용 용량으로 단독 투여되는 경우의 최상 요건 보다 현저하게 우수한 종양 세포 치사를 나타낸다면 치료적으로 상승적인 것으로 인정된다. 5배 미만의 종양 세포 치사의 차는 현저한 것으로 인정되지 않는다.Surprisingly, the combination of paclitaxel, taxotere or modified taxanes or taxoid analogs described herein with compounds having Formula (I) described herein provides enhanced or therapeutically elevated in vivo anticancer effects. It became. For the purposes of the present invention, two agents are recognized to be therapeutically synergistic if the combination treatment results in tumor cell death that is significantly better than the best requirement when the agent is administered alone at the optimal or maximum tolerated dose. Differences in tumor cell lethality of less than five times are not recognized as significant.
도면에는 화학식 (I)의 예로서 화합물 (i) 내지 (xvii)가 도시되어 있다.In the figures, compounds (i) to (xvii) are shown as examples of formula (I).
본 발명은 포유동물의 암을 치료하기에 유용한 약제 조성물에 관한 것이다. 본 발명의 약제 조성물은 2가지 화합물, 즉, 파클리택셀, 택소테레 또는 개질된 택산 또는 택소이드 유사체인 제 1 화합물 및 하기 추가 설명되는 화학식 (I)의 제 2 화합물을 포함한다. 각각의 화합물은 약제 조성물에서 유효량으로 존재한다. 1종 이상의 각각의 타입의 화합물은 약제 조성물에 존재할 수 있거나 통상적인 방법으로 투여될 수 있다. 본원에 사용된 용어 "유효량"은 원하는 생물학적 반응을 유도시키기에 충분한 양을 의미한다. 본 발명에 있어서, 원하는 생물학적 반응으로는 종양 또는 혈액학적 악성종양의 형성의 억제 (일부 또는 전부), 고형 종양 또는 기타 악성종양의 증식의 역전 또는 이것의 추가 진행의 방지 또는 감소가 있다.The present invention relates to pharmaceutical compositions useful for treating cancer in a mammal. The pharmaceutical composition of the present invention comprises two compounds, a first compound which is paclitaxel, taxotere or a modified taxane or taxoid analog and a second compound of formula (I) which is further described below. Each compound is present in an effective amount in the pharmaceutical composition. One or more of each type of compound may be present in the pharmaceutical composition or administered by conventional methods. As used herein, the term “effective amount” means an amount sufficient to elicit the desired biological response. In the present invention, the desired biological response is the inhibition (some or all) of the formation of a tumor or hematologic malignancy, the reversal of the proliferation of a solid tumor or other malignancy or the prevention or reduction of further progression thereof.
파클리택셀, 택소테레 또는 개질된 택산 또는 택소이드 유사체Paclitaxel, taxotere or modified taxanes or taxoid analogs
본 발명의 약제 조성물의 제 1 화합물의 한 가지 예인 파클리택셀(택솔(등록상표: Taxol))은 서양(태평양) 주목인 택수스 브레비폴리아(Taxus brevifolia)의 수피로부터 단리된 디테르펜이고, 택산 고리계를 갖는 치료제의 부류를 대표한다. 본 발명을 위해, 택산 고리계를 갖는 임의의 치료제는 "택산"으로서 규정된다. 파클리택셀의 화학식은 하기와 같다:Paclitaxel (Taxol), an example of a first compound of the pharmaceutical composition of the present invention, is a diterpene isolated from the bark of Taxus brevifolia of Western (Pacific) attention, Represents a class of therapeutic agents having a taxane ring system. For the purposes of the present invention, any therapeutic agent having a taxane ring system is defined as "taxane". The chemical formula of paclitaxel is as follows:
파클리택셀 및 이것의 유사체는 주목 침엽 및 잔가지로부터 수득되는 전구체인 10-데아세틸박카틴 III로부터의 부분 합성에 의해, 그리고 전체 합성에 의해 제조되었다 [참조: Holton, et al., J. Am. Chem. Soc. 116:1597-1601 (1994) 및 Nicolau, et al., Nature 367:630 (1994)]. 파클리택셀은 항종양 활성을 갖는 것으로 입증되었다. 보다 최근에는, 파클리택셀의 항종양 활성이 미세소관 중합의 촉진으로 인한 것으로 밝혀졌다 [참조: Kumar, N., J. Biol. Chem. 256:10435-10441 (1981); Rowinsky, et al., J. Natl. Cancer Inst. 82:1247-1259 (1990); 및 Schiff, et al., Nature 277:655-667 (1979)]. 파클리택셀은 임상 실험에서 다수의 사람 종양에 대한 효능이 입증되었다 [참조: McGuire, et al., Ann. Int. Med 111:237-279 (1989); Holmes, et al., J. Natl. Cancer Inst. 83:1797-1805 (1991); Kohn et al., J. Natl Cancer Inst. 86:18-24 (1994); 및 Kohn, et al., American Society for Clinical Oncology 12 (1993)]. 파클리택셀은 브리스톨-마이에르스 스큅 컴파니(Bristol-Myers Squibb Company, New York, NY)에 의해 등록 상표 택솔(Taxol)로 시판되고 있다.Paclitaxel and its analogs were prepared by partial synthesis from 10-deacetylbaccatin III, a precursor obtained from needles and twigs of interest, and by total synthesis. See Holton, et al., J. Am. . Chem. Soc. 116: 1597-1601 (1994) and Nicolau, et al., Nature 367: 630 (1994). Paclitaxel has been shown to have antitumor activity. More recently, the antitumor activity of paclitaxel was found to be due to the promotion of microtubule polymerization. Kumar, N., J. Biol. Chem. 256: 10435-10441 (1981); Rowinsky, et al., J. Natl. Cancer Inst. 82: 1247-1259 (1990); And Schiff, et al., Nature 277: 655-667 (1979). Paclitaxel has been demonstrated in clinical trials for a number of human tumors. McGuire, et al., Ann. Int. Med 111: 237-279 (1989); Holmes, et al., J. Natl. Cancer Inst. 83: 1797-1805 (1991); Kohn et al., J. Natl Cancer Inst. 86: 18-24 (1994); And Kohn, et al., American Society for Clinical Oncology 12 (1993). Paclitaxel is sold under the trademark Taxol by Bristol-Myers Squibb Company, New York, NY.
본 발명의 약제 조성물 중의 제 1 화합물은 파클리택셀(택솔), 택소테레 또는 개질된 택산 또는 택소이드 유사체인 것이 전형적이다. 개질된 택산 또는 택소이드 유사체는 개질된 측쇄를 함유하는 택산 고리를 갖는 화합물이다. 다수의 이들 유사체는 천연 파클리택셀의 특성 보다 개선된 특성, 예를 들어 높은 수용해도 및 안정성을 갖는다. 예를 들어, RPR109881은 론-포울렌 로레르(Rhon-Poulenc Rhorer)에 의해 개발 중이고, 현재 I기 임상 실험 중인 신규한 경구용 및 정맥용 활성 택소이드이다. 이들 유사체는 당업자에게 알려져 있고, 본원에 참고문헌으로 인용되어 있는 미국 특허 제 5,278,324호; 5,272,171호; 제 5,254,580호; 5,250,683호; 제 5,248,796호; 및 제 5,227,400호에 기재되어 있다. 택소테레는 본원에 참고문헌으로 인용되어 있는 WO 93/18210호에 기재된 방법에 의해 제조될 수 있다. 특정 구체예에 있어서, 본 발명의 약제 조성물의 제 1 화합물은 파클리택셀 또는 택소테레이다.The first compound in the pharmaceutical composition of the present invention is typically paclitaxel (taxol), taxotere or modified taxane or taxoid analogs. Modified taxanes or taxoid analogs are compounds having a taxane ring containing a modified side chain. Many of these analogs have properties that are improved over those of natural paclitaxel, such as high water solubility and stability. For example, RPR109881 is a novel oral and intravenous active taxoid under development by Rhon-Poulenc Rhorer and currently in Phase I clinical trials. These analogs are known to those of skill in the art and are described in US Pat. No. 5,278,324, which is incorporated herein by reference; 5,272,171; 5,254,580; 5,254,580; 5,250,683; No. 5,248,796; And 5,227,400. Taxotere may be prepared by the process described in WO 93/18210, which is incorporated herein by reference. In certain embodiments, the first compound of the pharmaceutical composition of the invention is paclitaxel or taxotere.
화학식 (I)의 화합물Compound of formula (I)
세포 증식 억제제로서의 현저한 활성을 갖는 다수의 짧은 펩티드가 인도양 군소인 돌라벨라 오리큘라리아(Dolabella auricularia)로부터 단리되었다 [참조: Bai, et al., Biochem. Pharmacology, 40: 1859-1864 (1990); Beckwith et al., J. Natl. Cancer Inst., 85: 483-488 (1993) 및 본원에 인용된 참고문헌]. 이들 펩티드로는 돌라스태틴 1 내지 10 (페티트(Pettit) 등의 미국 특허 제 4,816,444호) 및 돌라스태틴-15 (유럽 특허 출원 제 398558호)가 있다. 예를 들어, 돌라스태틴-15는 다양한 타입의 사람 악성종양에 대해 효능을 갖는 강력한 예보체(predictor)인 국립 암 학회의 P388 림프구 백혈병 세포계의 증식을 현저하게 억제시킨다. 그러나, 이 화합물은 군소 중에 미량으로만 존재하여, 단리하기가 어렵고, 합성 비용이 많이 들고, 수용해도가 불량하다.Many short peptides with remarkable activity as cell proliferation inhibitors have been isolated from the Indian Oceanic Dolabella auricularia. Bai, et al., Biochem. Pharmacology, 40: 1859-1864 (1990); Beckwith et al., J. Natl. Cancer Inst., 85: 483-488 (1993) and references cited therein]. These peptides include dolastatin 1-10 (US Pat. No. 4,816,444 to Pettit et al.) And dolastatin-15 (European patent application 398558). For example, dolastatin-15 significantly inhibits the proliferation of the P388 lymphocyte leukemia cell system of the National Cancer Society, a potent predictor that is potent against various types of human malignancies. However, this compound is present only in a small amount in a small amount, so that it is difficult to isolate, high synthesis cost, and poor water solubility.
화학식 (I)의 화합물은 돌라스태틴-15의 전술한 단점을 해결하면서 항종양 활성을 보유하거나 천연 생성물 보다 높은 항종양 활성을 나타내는 돌라스태틴-15의 유도체이다. 본 발명에서 파클리택셀, 택소테레 또는 개질된 택산 또는 택소이드 유사체와 조합된 형태로 사용되는 화학식 (I)의 돌라스태틴-15 유도체는 본원에 기재된 대로 합성되거나 본원에 참고문헌으로 인용되어 있는 1995년 6월 7일자 출원된 공동계류중인 관련 출원 U.S.S.N. 08/472,453호에 기재된 대로 합성될 수 있다.Compounds of formula (I) are derivatives of dolastatin-15 which solve the aforementioned disadvantages of dolastatin-15 while retaining antitumor activity or exhibiting higher antitumor activity than natural products. The dolastatin-15 derivatives of formula (I) used in the present invention in combination with paclitaxel, taxotere or modified taxanes or taxoid analogs are synthesized as described herein or incorporated herein by reference. Co-pending related application USSN, filed June 7, 1995 It can be synthesized as described in 08 / 472,453.
화학식 (I)의 돌라스태틴-15 유도체는 L 아미노산을 포함하는 것이 일반적이지만, 이들은 1995년 6월 7일자 출원된 공동계류중인 관련 출원 U.S.S.N. 08/472,453호에 기재된 1종 이상의 D 아미노산을 또한 함유할 수 있다. 화학식 (I)의 화합물은 생리적 허용 산, 예를 들어 이들에 제한되는 것은 아니지만, 염화수소산, 시트르산, 타르타르산, 락트산, 인산, 메탄술폰산, 아세트산, 포름산, 말레산, 푸마르산, 말산, 숙신산, 말론산, 황산, L 글루탐산, L 아스파르트산, 피루브산, 무크산, 벤조산, 글루쿠론산, 옥살산, 아스코르브산 및 아세틸글리신과의 염으로서 존재할 수 있다.It is common for dolastatin-15 derivatives of formula (I) to include L amino acids, but these are co-pending related applications U.S.S.N. filed June 7, 1995. It may also contain one or more D amino acids described in 08 / 472,453. Compounds of formula (I) include, but are not limited to, physiologically acceptable acids, such as hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, malic acid, succinic acid, malonic acid , Salts with sulfuric acid, L glutamic acid, L aspartic acid, pyruvic acid, muxic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid and acetylglycine.
본 발명에 사용된 "1가 라디칼"이란 용어는 제 2의 중성 분자 단편과 하나의 공유결합을 형성할 수 있는 전기적 중성 분자 단편을 의미하고자 한다. 1가 라디칼로는 수소 원자, 알킬 그룹 (예를 들어, 메틸, 에틸, 프로필 및 3차 부틸 그룹), 시클로알킬 그룹, 히드록시 알킬 그룹, 아다만틸 그룹, 할로겐 원자 (예를 들어, 불소, 염소 및 브롬 원자), 아릴 그룹 (예를 들어, 페닐, 벤질 및 나프틸 그룹) 및 알콕시 그룹 (예를 들어, 메톡시 및 에톡시 그룹)이 있다. 인접 시그마 결합된 원자들에 있는 2개의 1가 라디칼은 인접 원자들 간에 파이 결합을 또한 형성시킬 수 있다. 2개의 1가 라디칼은 예를 들어, 폴리메틸렌 단위에 의해 또한 함께 결합되어, 고리 구조물을 형성할 수 있다. 예를 들어, R 및 R′이 1가 라디칼인 단위 -N(R)R′은 질소 원자와 함께 결합하여, 헤테로시클릭 고리를 형성할 수 있다. 또한, 동일한 원자에 결합된 2개의 1가 라디칼은 2가 라디칼, 예를 들어 알킬리덴 그룹, 예를 들어 프로필리덴 그룹, 또는 산소 원자를 또한 형성할 수 있다.As used herein, the term "monovalent radical" is intended to mean an electrically neutral molecular fragment capable of forming one covalent bond with a second neutral molecular fragment. Monovalent radicals include hydrogen atoms, alkyl groups (eg methyl, ethyl, propyl and tertiary butyl groups), cycloalkyl groups, hydroxy alkyl groups, adamantyl groups, halogen atoms (eg fluorine, Chlorine and bromine atoms), aryl groups (eg phenyl, benzyl and naphthyl groups) and alkoxy groups (eg methoxy and ethoxy groups). Two monovalent radicals in adjacent sigma bonded atoms can also form pi bonds between adjacent atoms. Two monovalent radicals may also be joined together, for example by polymethylene units, to form a ring structure. For example, the unit -N (R) R ', wherein R and R' are a monovalent radical, may combine with a nitrogen atom to form a heterocyclic ring. In addition, two monovalent radicals bonded to the same atom may also form a divalent radical, for example an alkylidene group, for example a propylidene group, or an oxygen atom.
더욱 상세하게는, 화학식 (I)의 화합물에 있어서,More specifically, in the compound of formula (I),
R1은 알킬, 예를 들어 C1-C3; 시클로알킬, 예를 들어 시클로프로필; 알킬술포닐, 예를 들어 C1-C3; 플루오로알킬, 예를 들어 플루오로에틸, 디플루오로에틸, 플루오로이소프로필; 알킬, 예를 들어 메틸에 의해 치환될 수 있는 아미노술포닐이고;R 1 is alkyl, eg C 1 -C 3 ; Cycloalkyl such as cyclopropyl; Alkylsulfonyl such as C 1 -C 3 ; Fluoroalkyls such as fluoroethyl, difluoroethyl, fluoroisopropyl; Aminosulfonyl which may be substituted by alkyl such as methyl;
R2는 수소; 알킬, 예를 들어 C1-C3; 플루오로알킬, 예를 들어 플로오로에틸, 디플루오로에틸, 플루오로이소프로필; 시클로알킬, 예를 들어 시클로프로필이고;R 2 is hydrogen; Alkyl such as C 1 -C 3 ; Fluoroalkyls such as fluoroethyl, difluoroethyl, fluoroisopropyl; Cycloalkyl, for example cyclopropyl;
R1-N-R2는 함께 결합하여 피롤리디노 또는 피페리디노 잔기를 형성할 수 있고;R 1 -NR 2 may be joined together to form a pyrrolidino or piperidino residue;
A는 발릴, 이소루실, 루실, 알로-이소루실, 2,2-디메틸글리실, 2-시클로프로필글리실, 2-시클로펜틸글리실, 3-3차부틸알라닐, 2-3차부틸글리실, 3-시클로헥실알라닐, 2-에틸글리실, 2-시클로헥실글리실, 노르루실 또는 노르발릴 잔기이고;A is valeryl, isoleucyl, lusyl, allo-isorusil, 2,2-dimethylglycyl, 2-cyclopropylglycyl, 2-cyclopentylglycyl, 3-tert-butylalanyl, 2-3 tert-butyl Lysyl, 3-cyclohexylalanyl, 2-ethylglycyl, 2-cyclohexylglycyl, norrucil or norvalyl moiety;
B는 N-알킬-발릴, -노르발릴, -루실, -이소루실, 2-3차부틸글리실, -3-3차부틸알라닐, -2-에틸글리실, -2-시클로프로필글리실, -2-시클로펜틸글리실, 노르루실 또는 -2-시클로헥실글리실 잔기이며, 여기서, N-알킬은 바람직하게는 N-메틸 또는 N-에틸이고;B is N-alkyl-valyl, -norvalyl, -rucil, -isorucil, 2-3 tertiary butyl glycyl, -3 tertiary butylalanyl, -2-ethylglycyl, -2-cyclopropylglycyl , -2-cyclopentylglycyl, norrucil or -2-cyclohexylglycidyl moiety, wherein N-alkyl is preferably N-methyl or N-ethyl;
D는 프롤릴, 호모프롤릴, 히드록시프롤릴, 3,4-데히드로프롤릴, 4-플루오로프롤릴, 3-메틸프롤릴, 4-메틸프롤릴, 5-메틸프롤릴, 아제티딘-2-카르보닐, 3,3-디메틸프롤릴, 4,4-디플루오로프롤릴, 옥사졸리딘-4-카르보닐 또는 티아졸리딘-4-카르보닐 잔기이고;D is prolyl, homoprolyl, hydroxyprolyl, 3,4-dehydroprolyl, 4-fluoroprolyl, 3-methylprolyl, 4-methylprolyl, 5-methylprolyl, azetidine-2 -Carbonyl, 3,3-dimethylprolyl, 4,4-difluoroprolyl, oxazolidine-4-carbonyl or thiazolidine-4-carbonyl residues;
E는 프롤릴, 호모프롤릴, 히드록시프롤릴, 3,4-데히드로프롤릴, 4-플루오로프롤릴, 3-메틸프롤릴, 4-메틸프롤릴, 5-메틸프롤릴, 아제티딘-2-카르보닐, 3,3-디메틸프롤릴, 4,4-디플루오로프롤릴, 옥사졸리딘-4-카르보닐 또는 티아졸리딘-4-카르보닐 잔기이고;E is prolyl, homoprolyl, hydroxyprolyl, 3,4-dehydroprolyl, 4-fluoroprolyl, 3-methylprolyl, 4-methylprolyl, 5-methylprolyl, azetidine-2 -Carbonyl, 3,3-dimethylprolyl, 4,4-difluoroprolyl, oxazolidine-4-carbonyl or thiazolidine-4-carbonyl residues;
F와 G는 프롤릴, 호모프롤릴, 히드록시프롤릴, 티아졸리디닐-4-카르보닐, 1-아미노펜틸-1-카르보닐, 발릴, 2-3차부틸글리실, 이소루실, 루실, 3-시클로헥실알라닐, 페닐알라닐, N-메틸페닐알라닐, 테트라히드로시오퀴놀릴-2-히스티딜, 1-아미노인딜-1-카르보닐, 3-피리딜알라닐, 2-시클로헥실글리실, 노르루실, 노르발릴, 네오펜틸글리실, 트리토파닐, 글리실, 2,2-디메틸글리실 알라닐, β-알라닐 및 3-나프틸알라닐 잔기로 구성된 군으로부터 각각 선택되고;F and G are prolyl, homoprolyl, hydroxyprolyl, thiazolidinyl-4-carbonyl, 1-aminopentyl-1-carbonyl, valeryl, 2-3 tert-butyl glycyl, isoleucyl, rusil, 3-cyclohexylalanyl, phenylalanyl, N-methylphenylalanyl, tetrahydrothioquinolyl-2-histidyl, 1-aminoindyl-1-carbonyl, 3-pyridylalanyl, 2-cyclohexyl Silglysil, norrucil, norvalyl, neopentylglysil, tritopanyl, glycyl, 2,2-dimethylglycyl alanyl, β-alanyl and 3-naphthylalanyl residues, respectively; ;
X는 수소, 알킬 (예를 들어 C1-C5), 시클로알킬 (C3-C7), -CH2-시클로헥실 또는 아릴알킬 (예를 들어, 벤질 또는 페네틸)이고;X is hydrogen, alkyl (eg C 1 -C 5 ), cycloalkyl (C 3 -C 7 ), -CH 2 -cyclohexyl or arylalkyl (eg benzyl or phenethyl);
s, t 및 u는 각각 0 또는 1이고;s, t and u are each 0 or 1;
K는 히드록시, 알콕시 (예를 들어, C1-C4), 페녹시, 벤질옥시 또는 치환되거나 비치환된 아미노 부분이다.K is hydroxy, alkoxy (eg C 1 -C 4 ), phenoxy, benzyloxy or substituted or unsubstituted amino moieties.
또한, 화학식 (I)의 화합물은 생리학적 허용 산과의 염으로서 존재할 수 있다.In addition, compounds of formula (I) may exist as salts with physiologically acceptable acids.
본 발명의 화합물의 한 가지 서브클래스로는 R1-N-R2이 피롤리디닐 또는 피페리디닐 잔기인 화학식 (I)의 화합물이 있다.One subclass of compounds of the present invention is compounds of formula (I), wherein R 1 -NR 2 is a pyrrolidinyl or piperidinyl residue.
본 발명의 화합물의 또 다른 서브클래스로는 K가 화학식 R5-N-R6의 아미노 부분인 화학식 (I)의 화합물이 있으며, 여기서,Another subclass of compounds of the present invention are compounds of formula (I), wherein K is the amino portion of formula R 5 -NR 6 , wherein
R5는 수소, 또는 히드록시, C 알콕시, 또는 벤질옥시, 또는 페닐옥시 또는 C1-7직쇄 또는 측쇄 히드록시알킬, 예를 들어 3-히드록시-1,1-디메틸프로필, 또는 C1-12직쇄 또는 측쇄 알킬 (하나 이상의 불소 원자에 의해 치환될 수 있음), 또는 C1-7시클로알킬, 예를 들어 비시클로[3.3.0]옥타-1일, 1-메틸시클로펜틸 또는 1-메틸시클로헥실; 또는 벤질 (각각 CF3, 니트로, C1-7알킬술포닐, C1-4알콕시, 페녹시, 벤족시, 할로겐, C1-4알킬, 시아노, 히드록시, N(CH3)2, COOMe, COOEt, COOiPr, 또는 COONH2일 수 있는 3개 이하의 치환기에 의해 치환될 수 있음)이고;R 5 is hydrogen or hydroxy, C alkoxy, or benzyloxy, or phenyloxy or C 1-7 linear or branched hydroxyalkyl, for example 3-hydroxy-1,1-dimethylpropyl, or C 1- 12 straight or branched chain alkyl (which may be substituted by one or more fluorine atoms), or C 1-7 cycloalkyl, for example bicyclo [3.3.0] octa-1yl, 1-methylcyclopentyl or 1-methyl Cyclohexyl; Or benzyl (CF 3 , nitro, C 1-7 alkylsulfonyl, C 1-4 alkoxy, phenoxy, benzoxyl, halogen, C 1-4 alkyl, cyano, hydroxy, N (CH 3 ) 2 , COOMe, COOEt, COOiPr, or COONH 2 , which may be substituted by up to 3 substituents);
R6은 수소, 또는 C1-12직쇄 또는 측쇄 알킬 (하나 이상의 불소 원자에 의해 치환될 수 있음), 또는 C1-12직쇄 또는 측쇄 히드록시알킬, 예를 들어 3-히드록시-1,1-디메틸프로필, 또는 C3-10-시클로알킬, 예를 들어 비시클로[3.3.0]옥타-1-일, 또는 1-메틸시클로펜틸 또는 1-메틸시클로헥실; 또는 -(CH2)v-C3-7-시클로알킬 (v = 0, 1, 2 또는 3), 또는 노르에페드릴, 또는 노르슈도에페드릴, 또는 퀴놀릴, 또는 피라질, 또는 -CH2-벤즈이미다졸릴, 또는 (1)-아만틸, 또는 (2)-아만틸- -CH2-아만틸, 또는 알파-메틸-벤질, 또는 알파-디메틸벤질, 또는 -(CH2)v-페닐 (v = 0, 1, 2 또는 3 이고, 각각 CF3, 니트로, C1-7알킬술포닐, C1-4알콕시, 페녹시, 벤족시, 할로겐, 고리계를 형성할 수 있는 C1-4알킬, 시아노, 히드록시, N(CH3)2, COOMe, COOEt, COOiPr, 또는 COONH2일 수 있는 2개 이하의 치환기에 의해 치환될 수 있음), 또는 -(CH2)m-나프틸 (m = 0 또는 1); 또는 -(CH2)w-벤즈히드릴 (w = 0, 1 또는 2); 또는 비페닐 또는 피콜릴 또는 벤조티아졸릴 또는 벤조이소티아졸릴 또는 벤조피라졸릴 또는 벤조옥사졸릴 또는 -(CH2)m-플루오레닐 (m = 0 또는 1); 또는 피리미딜 또는 -(CH2)m-인다닐 (m = 0 또는 1); 또는 -(CH2CH2O)y-CH3(y = 0,1,2,3,4, 또는 5), 또는 -(CH2CH2O)y-CH2CH3((y = 0,1,2,3,4, 또는 5), 또는 NH-C6H5(각각 CF3, 니트로, C1-7알킬술포닐, C1-4알콕시, 페녹시, 벤족시, 할로겐, 고리계를 형성할 수 있는 C1-4알킬, 시아노, 히드록시, N(CH3)2, COOMe, COOEt, COOiPr, 또는 COONH2일 수 있는 2개 이하의 치환기에 의해 치환될 수 있음), 또는 NCH3-C6H5또는 NH-CH2-C6H5또는 NCH3-CH2-C6H5또는 헤테로고리인 페닐과 2고리계를 형성하는, 각각 CF3, 니트로, 티오메틸, 티오에틸, C3-6시클로알킬, -CH2-COOEt, C3-4알킬렌 그룹일 수 있는 2개 이하의 치환기에 의해 치환될 수 있는 5원 헤테로아릴; 또는 -CHR7-5원 헤테로아릴 (각각 CF3, 니트로, 시아노, 할로겐, COOMe, COOEt, COOiPr, CONH2, C1-4알킬, C1-4알콕시, 페닐, 벤질, 나프틸, 또는 C1-7알킬술포닐일 수 있는 2개 이하의 치환기에 의해 치환될 수 있으며; R7은 수소, 직쇄 또는 측쇄 C1-5알킬, 벤질이거나; R7과 R5는 함께 결합하여 -(CH2)3- 또는 -(CH2)4-를 형성함)이다.R 6 is hydrogen, or C 1-12 straight or branched chain alkyl (which may be substituted by one or more fluorine atoms), or C 1-12 straight or branched chain hydroxyalkyl, for example 3-hydroxy-1,1 -Dimethylpropyl, or C 3-10 -cycloalkyl, for example bicyclo [3.3.0] octa-1-yl, or 1-methylcyclopentyl or 1-methylcyclohexyl; Or-(CH 2 ) v -C 3-7 -cycloalkyl (v = 0, 1, 2 or 3), or norefedrill, or norsudoephedryl, or quinolyl, or pyrazyl, or -CH 2 Benzimidazolyl, or (1) -amantyl, or (2) -amantyl--CH 2 -amantyl, or alpha-methyl-benzyl, or alpha-dimethylbenzyl, or-(CH 2 ) v- -phenyl (v = 0, 1, 2 or 3, respectively, CF 3, nitro, C 1-7 alkylsulfonyl, C 1-4 alkoxy, phenoxy C 1 capable of forming, when l, halogen, ring system -4 may be substituted by up to 2 substituents which may be alkyl, cyano, hydroxy, N (CH 3 ) 2 , COOMe, COOEt, COOiPr, or COONH 2) , or-(CH 2 ) m- Naphthyl (m = 0 or 1); Or-(CH 2 ) w -benzhydryl (w = 0, 1 or 2); Or biphenyl or picolyl or benzothiazolyl or benzoisothiazolyl or benzopyrazolyl or benzooxazolyl or-(CH 2 ) m -fluorenyl (m = 0 or 1); Or pyrimidyl or-(CH 2 ) m -indanyl (m = 0 or 1); Or-(CH 2 CH 2 O) y -CH 3 (y = 0,1,2,3,4, or 5), or-(CH 2 CH 2 O) y -CH 2 CH 3 ((y = 0 , 1,2,3,4, or 5), or NH-C 6 H 5 (CF 3 , nitro, C 1-7 alkylsulfonyl, C 1-4 alkoxy, phenoxy, benzoxyl, halogen, ring May be substituted by up to 2 substituents which may be C 1-4 alkyl, cyano, hydroxy, N (CH 3 ) 2 , COOMe, COOEt, COOiPr, or COONH 2 which may form a system), Or CF 3 , nitro, thiomethyl, which form a bicyclic system with NCH 3 -C 6 H 5 or NH-CH 2 -C 6 H 5 or NCH 3 -CH 2 -C 6 H 5 or heterocyclic phenyl, respectively 5 membered heteroaryl which may be substituted by up to 2 substituents which may be thioethyl, C 3-6 cycloalkyl, -CH 2 -COOEt, C 3-4 alkylene group; or -CHR 7 -5 member Heteroaryl (CF 3 , nitro, cyano, halogen, COOMe, COOEt, COOiPr, CONH 2 , C 1-4 alkyl, C 1-4 alkoxy, phenyl, benzyl, naphthyl, or C 1-7 alkylsulfonylyl 2 teeth which can And R 7 is hydrogen, straight or branched C 1-5 alkyl, benzyl; R 7 and R 5 are bonded together to form-(CH 2 ) 3 -or-(CH 2 ) 4- To form).
이 서브클래스로는 s,t 및 u가 각각 0 또는 1이고; R1, R2및 X가 저급 알킬이고, A가 저급 알킬 아미노산이고; B가 N-저급알킬화된 저급 알킬 아미노산이고; D,E,F,G 및 K가 상기 규정된 바와 같은 화학식 (I)의 화합물이 있다. 상기를 염두해 두면, 이러한 화합물의 세 가지 세트가 하기 화학식 (II), (III) 및 (IV)에 의해 표현될 수 있다:For this subclass s, t and u are each 0 or 1; R 1 , R 2 and X are lower alkyl and A is lower alkyl amino acid; B is N-lower alkylated lower alkyl amino acid; There are compounds of formula (I) wherein D, E, F, G and K are as defined above. With the above in mind, three sets of such compounds can be represented by the following formulas (II), (III) and (IV):
-CHR7-5원 헤테로아릴은 예를 들어, 하기 잔기 중의 하나에 의해 표현될 수 있다:-CHR 7 -5-membered heteroaryl may be represented by one of, for example, to moieties:
-NR5CHR7-5원 헤테로아릴은 예를 들어, 하기 잔기에 의해 표현될 수 있다:-NR 5 CHR 7 -5-membered heteroaryl may be, for example, represented by the following residues:
5원 헤테로아릴은 예를 들어, 하기 잔기에 의해 표현될 수 있다:5-membered heteroaryl can be represented, for example, by the following residues:
본 발명의 화합물의 또 다른 서브클래스에 있어서, R5-N-R6은 함께 결합하여 하기 구조로 구성된 군으로부터 선택되는 구조를 형성할 수 있다:In another subclass of the compounds of the invention, R 5 -NR 6 may be bonded together to form a structure selected from the group consisting of:
본 발명의 화합물의 또 다른 서브클래스로는 예를 들어, s, t 및 u가 1이고, K가 히드록시, 알콕시, 페녹시 또는 벤질옥시 부분인 화학식 (I)의 화합물이 있다.Another subclass of compounds of the invention is, for example, compounds of formula (I) wherein s, t and u are 1 and K is a hydroxy, alkoxy, phenoxy or benzyloxy moiety.
본 발명의 화합물의 또 다른 서브클래스로는 예를 들어, s와 t가 1이고, u가 0이고, K가 히드록시, 알콕시, 페녹시 또는 벤질옥시 부분인 화학식 (I)의 화합물이 있다.Another subclass of compounds of the invention is, for example, compounds of formula (I) wherein s and t are 1, u is 0 and K is a hydroxy, alkoxy, phenoxy or benzyloxy moiety.
본 발명의 화합물의 또 다른 서브클래스로는 s가 1이고, t와 u가 0이고, K가 히드록시, 알콕시, 페녹시 또는 벤질옥시 부분인 화학식 (I)의 화합물이 있다.Another subclass of compounds of the present invention is compounds of formula (I) wherein s is 1, t and u are 0 and K is a hydroxy, alkoxy, phenoxy or benzyloxy moiety.
특정 구체예에 있어서, 본 발명의 약제 조성물 중의 제 2 화합물은 화학식 (I)의 화합물로서, R1과 R2는 각각 메틸 또는 에틸이고; X가 이소프로필, 2차 부틸 또는 3차 부틸이고; s가 1이고; t와 u가 각각 0이고; A가 발릴, 이소루실 또는 2-3차부틸글리실이고; B가 N-메틸발릴, 1-이소루실 또는 -2-3차부틸글리실이고; D가 프롤릴, 티아졸리디닐-4-카르보닐 또는 3,4 데히드로프롤릴이고; E가 프롤릴, 티아졸리디닐-4-카르보닐, 호모프롤릴, 3,4-데히드로프롤릴 또는 히드록시프롤릴이고; K가 화학식 R5-N-R6을 갖는 치환되거나 비치환된 아미노 부분이다.In certain embodiments, the second compound in the pharmaceutical composition of the present invention is a compound of Formula (I), wherein R 1 and R 2 are each methyl or ethyl; X is isopropyl, secondary butyl or tertiary butyl; s is 1; t and u are each 0; A is valeryl, isoleucyl or 2-3 tertiary butyl glycyl; B is N-methylvalyl, 1-isosilyl or 2-tert-butylglycyl; D is prolyl, thiazolidinyl-4-carbonyl or 3,4 dehydroprolyl; E is prolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; K is a substituted or unsubstituted amino moiety having the formula R 5 -NR 6 .
또 다른 구체예에 있어서, 본 발명의 약제 조성물 중의 제 2 화합물은 화학식 (I)의 화합물로서, R1과 R2가 각각 메틸 또는 에틸이고; X는 이소프로필, 2차 부틸 또는 3차 부틸이고; s는 1이고; t와 u는 각각 0이고; A는 발릴, 이소루실 또는 2-3차부틸글리실이고; D는 프롤릴, 티아졸리디닐-4-카르보닐, 또는 3,4-데히드로프롤릴이고; E는 프롤릴, 티아졸리디닐-4-카르보닐, 호모프롤릴, 3,4-데히드로프롤릴 또는 히드록시프롤릴이고; K는 화학식 R5-N-R6을 갖는 치환된 아미노 부분이며, 여기서, R5는 수소 또는 C1-C4알콕시이고, R6는 예를 들어 하기 1가 라디칼에 의해 표현되는 C1-C12직쇄 또는 측쇄 알킬 그룹 또는 C1-C13직쇄 또는 측쇄 히드록시알킬 그룹이다:In another embodiment, the second compound in the pharmaceutical composition of the present invention is a compound of formula (I), wherein R 1 and R 2 are each methyl or ethyl; X is isopropyl, secondary butyl or tertiary butyl; s is 1; t and u are each 0; A is valeryl, isoleucyl or 2-3 tert-butylglycyl; D is prolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; E is prolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; K is a substituted amino moiety having the formula R 5 -NR 6 , wherein R 5 is hydrogen or C 1 -C 4 alkoxy and R 6 is for example represented by C 1 -C 12 represented by the following monovalent radicals: Straight or branched chain alkyl groups or C 1 -C 13 straight or branched chain hydroxyalkyl groups:
3-히드록시-1,1-디메틸프로필로서 또한 명명되는 -C(CH3)2-CH2-CH2-OH;-C (CH 3 ) 2 -CH 2 -CH 2 -OH, also referred to as 3-hydroxy-1,1-dimethylpropyl;
3차 부틸로서 또한 명명되는 C(CH3)3;C (CH 3 ) 3 , also named as tertiary butyl;
1,1-디메틸프로필로서 또한 명명되는;Also named as 1,1-dimethylpropyl ;
1-메틸-1-에틸프로필로서 또한 명명되는;Also named as 1-methyl-1-ethylpropyl ;
(S)- 또는 (R)-1-메틸-2,2-디메틸-프로필로서 또한 명명되는;Also named as (S)-or (R) -1-methyl-2,2-dimethyl-propyl ;
(S)- 또는 (R)-1-에틸-2-메틸프로필로서 또한 명명되는;Also named as (S)-or (R) -1-ethyl-2-methylpropyl ;
1-이소프로필-2-메틸-프로필로서 또한 명명되는; 또는Also named as 1-isopropyl-2-methyl-propyl ; or
1,1-디메틸-2-메틸프로필로서 또한 명명되는 -C(CH3)2-CH(CH3)2;-C (CH 3 ) 2 -CH (CH 3 ) 2 , also named as 1,1-dimethyl-2-methylpropyl;
이소프로필로서 또한 명명되는 -CH(CH3)2;-CH (CH 3 ) 2 , also named as isopropyl;
2차 부틸 [(S) 또는 (R)]로서 또한 명명되는 -CH(CH3)CH2CH3; 또는-CH (CH 3 ) CH 2 CH 3 , also referred to as secondary butyl [(S) or (R)]; or
-1,2-디메틸프로필로서 또한 명명되는 -CH(CH3)CH(CH3)2.-CH (CH 3 ) CH (CH 3 ) 2 , also named as -1,2-dimethylpropyl.
또 다른 구체예에 있어서, 본 발명의 약제 조성물 중의 제 2 화합물은 화학식 (I)의 화합물로서, R1과 R2는 각각 메틸 또는 에틸이고; X는 이소프로필, 2차 부틸 또는 3차 부틸이고; s는 1이고; t와 u는 각각 0이고; A는 발릴, 이소루실 또는 2-3차부틸글리실이고; B는 N-메틸발릴, 1-이소루실 또는 2-3차부틸글리실이고; D는 프롤릴, 티아졸리디닐-4-카르보닐, 3,4-데히드로프롤릴이고; E는 프롤릴, 티아졸리디닐-4-카르보닐, 호모프롤릴, 3,4-데히드로프롤릴 또는 히드록시프롤릴이고; K는 화학식 R5-N-R6을 갖는 치환된 아미노 부분이며, 여기서, R5는 수소 또는 C1-C4알콕시이고, R는 1가 라디칼, 예를 들어 C3-C10시클로알킬 그룹 (예를 들어, 시클로부틸, 시클로펜틸, 시클로헥실 또는 1-메틸시클로펜틸, 또는 1-메틸시클로헥실 또는 비시클로[3.3.0]옥타-1-일); (1)- 또는 (2)-아다만틸 그룹; v가 1 또는 α,α-디메틸벤질인 (CH2)v-페닐이다.In another embodiment, the second compound in the pharmaceutical composition of the present invention is a compound of formula (I), wherein R 1 and R 2 are each methyl or ethyl; X is isopropyl, secondary butyl or tertiary butyl; s is 1; t and u are each 0; A is valeryl, isoleucyl or 2-3 tert-butylglycyl; B is N-methylvalyl, 1-isosilyl or 2-3 tert-butylglycyl; D is prolyl, thiazolidinyl-4-carbonyl, 3,4-dehydroprolyl; E is prolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; K is a substituted amino moiety having the formula R 5 -NR 6 , wherein R 5 is hydrogen or C 1 -C 4 alkoxy and R is a monovalent radical such as a C 3 -C 10 cycloalkyl group (eg For example, cyclobutyl, cyclopentyl, cyclohexyl or 1-methylcyclopentyl, or 1-methylcyclohexyl or bicyclo [3.3.0] octa-1-yl); (1)-or (2) -adamantyl groups; (CH 2 ) v-phenyl, where v is 1 or α, α-dimethylbenzyl.
또 다른 구체예에 있어서, 본 발명의 약제 조성물 중의 제 2 화합물은 화학식 (I)의 화합물로서, R1과 R2는 각각 메틸이고; X는 이소프로필이고; s는 1이고; t와 u는 각각 0이고; A는 발릴이고; B는 N-메틸발릴이고; D는 프롤릴이고; E는 프롤릴이고; K는 화학식 R5-N-R6을 갖는 치환된 아미노 부분이며, 여기서, R5는 벤질이고, R6은 수소이다. 이 화합물은 도면에 도시된 화합물 (xvii)에 상응한다. 화학식 (I)의 화합물 (xvii)을 파클리택셀과 조합하여 사용한 결과를 표 1 내지 4에 나타내었다.In another embodiment, the second compound in the pharmaceutical composition of the present invention is a compound of formula (I), wherein R 1 and R 2 are each methyl; X is isopropyl; s is 1; t and u are each 0; A is valeryl; B is N-methylvalyl; D is prolyl; E is prolyl; K is a substituted amino moiety having the formula R 5 -NR 6 , wherein R 5 is benzyl and R 6 is hydrogen. This compound corresponds to compound (xvii) shown in the figure. The results of using compound (xvii) of formula (I) in combination with paclitaxel are shown in Tables 1-4.
본 발명의 약제 조성물은 임의로 약제학적 허용 담체를 함유할 수 있다. 약제학적 허용 담체는 당업자에게 널리 알려져 있다. 담체의 선택은 조합물 중의 특정 화합물 뿐만 아니라 약제 조성물을 투여하는 데에 사용된 특정 방법에 의해 부분적으로 결정될 수 있다. 따라서, 본 발명의 약제 조성물의 적당한 제형은 광범위하게 존재한다. 예를 들어, 파클리택셀(Taxol)은 폴리옥시에틸화된 파마자유 (Cremophor EL)와 탈수 알코올인 USP를 포함하는 무균 비발열성 용액으로서 사용될 수 있다.Pharmaceutical compositions of the invention may optionally contain a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known to those skilled in the art. The choice of carrier can be determined in part by the particular method used to administer the pharmaceutical composition as well as the particular compound in the combination. Accordingly, suitable formulations of the pharmaceutical compositions of the present invention are broadly present. For example, paclitaxel (Taxol) can be used as a sterile, nonpyrogenic solution comprising polyoxyethylated Pharmaza Oil (Cremophor EL) and USP, a dehydrating alcohol.
또 다른 일면에 있어서, 본 발명은 포유동물에게 유효량의 제 1 화합물, 즉, 파클리택셀, 택소테레 또는 개질된 택산 또는 택소이드 유사체를 투여하고, 화학식 (I)의 화합물인 유효량의 제 2 화합물을 투여함으로써, 포유동물, 예를 들어 사람에게서, 고형 종양 (예를 들어, 폐, 유방, 결장, 전립선, 방광, 직장 또는 자궁내막의 종양) 또는 혈액학적 악성종양 (예를 들어, 백혈병, 림프종)의 형성을 부분 또는 완전 억제시키거나 치료하는 (예를 들어, 고형 종양 추가 발생을 역전시키거나 억제시키는) 방법을 포함한다.In another aspect, the invention provides an effective amount of a second compound to a mammal, the effective amount of the first compound being administered to the mammal, ie, paclitaxel, taxotere, or modified taxanes or taxoid analogs, the compound of formula (I) By administering to a solid tumor (e.g., a tumor of the lung, breast, colon, prostate, bladder, rectum or endometrium) or a hematologic malignancy (e.g. leukemia, lymphoma) in a mammal, for example a human ) Partially or completely inhibiting or treating the formation of (eg, reversing or inhibiting solid tumor further development).
두 가지 화합물은 본 발명에 따라 조합된 형태로 투여된다. 여기서, 조합된 형태란 용어는 약제가 동시 또는 순차 투여됨을 의미한다. 순차 투여되는 경우, 두 가지 화합물 중의 하나는 나머지 화합물의 투여시에 대상의 혈청에서 검출가능한 것이 일반적이다. 한 구체예에 있어서, 먼저 화합물 (I)의 화합물이 투여된 후, 전술된 제 1 화합물, 예를 들어 파클리택셀이 투여된다. 특정 구체예에 있어서, 파클리택셀은 화학식 (I)의 화합물이 투여된 지 약 1시간 후에 투여된다. 다른 방법으로는, 제 1 화합물과 제 2 화합물은 동시 투여될 수 있거나, 먼저 제 1 화합물이 투여된 후, 화학식 (I)의 화합물인 제 2 화합물이 투여될 수 있다.The two compounds are administered in combined form in accordance with the present invention. Here, the term combined form means that the agents are administered simultaneously or sequentially. When administered sequentially, one of the two compounds is generally detectable in the subject's serum upon administration of the other compound. In one embodiment, the compound of compound (I) is first administered followed by the first compound described above, for example paclitaxel. In certain embodiments, paclitaxel is administered about 1 hour after the compound of Formula (I) is administered. Alternatively, the first compound and the second compound may be co-administered, or the first compound may be administered first, followed by the second compound, which is a compound of formula (I).
제 1 및 제 2 화합물은 단독 투여되거나 원하는 투여 경로에 적합한 약제학적 허용 담체 또는 희석제와 함께 투여될 수 있다. 투여는, 경구 투여 및 피하, 정맥내, 근내, 복강내, 비강 또는 직장 투여와 같은 비경구 투여를 포함하여, 약제, 바람직하게는 종양학적 제제 분야에서는 통상적인 수단 선택되는 하나에 의해 수행될 수 있다. 이러한 약제 조성물은 그 밖의 약제학적 활성 성분을 또한 함유할 수 있다.The first and second compounds may be administered alone or in combination with a pharmaceutically acceptable carrier or diluent suitable for the desired route of administration. Administration may be carried out by any one of ordinary skill in the art of pharmaceuticals, preferably oncological agents, including oral administration and parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, nasal or rectal administration. have. Such pharmaceutical compositions may also contain other pharmaceutically active ingredients.
포유동물, 예를 들어 사람에게 투여되는 용량은, 본원에 기재된 바와 같이, 유효량의 화학식 (I)의 화합물과 유효량의 파클리택셀, 택소테레 또는 개질된 택산 또는 택소이드 유사체의 결합량을 포함한다. 특정 질환 또는 치료 방법의 경우, 용량은 공지된 방법을 사용하여 실험적으로 결정될 수 있으며, 예를 들어, 사용된 특정 화합물의 생물학적 활성, 작용 메카니즘, 교차 저항성, 중복 독성 및 독성 프로파일; 투여의 수단; 대상의 연령, 건강 상태 및 체중; 증상의 성질과 정도; 치료의 빈도; 다른 치료제의 투여; 및 원하는 효과와 같은 인자에 좌우될 것이다.Doses administered to a mammal, such as a human, include a combined amount of an effective amount of a compound of Formula (I) and an effective amount of paclitaxel, taxotere or modified taxane or taxoid analog, as described herein. . For certain diseases or methods of treatment, doses can be determined experimentally using known methods, including, for example, the biological activity, mechanism of action, cross resistance, overlapping toxicity and toxicity profile of the specific compound used; Means of administration; The age, health status and weight of the subject; Nature and extent of symptoms; Frequency of treatment; Administration of other therapeutic agents; And factors such as the desired effect.
화학식 (I)의 화합물의 전형적인 1일 용량은 경구 투여에 의해서는 체중 1㎏ 당 약 5 내지 약 250㎎ 이고, 비경구 투여에 의해서는 체중 1㎏ 당 약 1 내지 약 100㎎ 일 것이다. 파클리택셀, 택소테레 또는 개질된 택산 또는 택소이드 유사체의 전형적인 1일 용량은 1㎏ 당 5 내지 약 250㎎인 것이 일반적일 것이다.A typical daily dose of a compound of formula (I) will be about 5 to about 250 mg / kg body weight by oral administration and about 1 to about 100 mg / kg body weight by parenteral administration. Typical daily doses of paclitaxel, taxotere or modified taxanes or taxoid analogues will typically be from 5 to about 250 mg per kg.
본 발명의 제 1 및 제 2 화합물은 통상적인 고체상 또는 액상 약제 투여 형태, 예를 들어 비피복되거나 (필름)피복된 정제, 캡슐, 분말, 미립, 좌약 또는 용액으로 투여될 수 있다. 이들은 통상적인 방식으로 제조된다. 활성 물질은 이를 위해 통상적인 약제 보조제, 예를 들어 정제 결합제, 충전제, 방부제, 정제 분해제, 유동 조절제, 가소제, 습윤제, 분산제, 에멀션화제, 용매, 지연 방출 조성물, 산화방지제 및/또는 추진용 기체로 처리될 수 있다 (참조: H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). 이 방식으로 수득된 투여형은 약 1 내지 약 90 중량%의 활성 성분을 함유하는 것이 전형적이다.The first and second compounds of the present invention may be administered in conventional solid or liquid pharmaceutical dosage forms, such as uncoated or (film) coated tablets, capsules, powders, granules, suppositories or solutions. They are prepared in a conventional manner. The active substances can be used for this purpose in conventional pharmaceutical auxiliaries, for example tablet binders, fillers, preservatives, tablet disintegrators, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, delayed release compositions, antioxidants and / or propellant gases. (H. Sucker et al .: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). Dosage forms obtained in this manner typically contain about 1 to about 90% by weight of active ingredient.
화학식 (I)의 화합물은 상세하게 전술되어 있다. 특정 구체예에 있어서, 본 발명의 방법은 화학식 (I)의 화합물로서, R1및 R2가 각각 메틸 또는 에틸이고; X가 이소프로필, 2차 부틸 또는 3차 부틸이고; s가 1이고; t 및 u가 각각 0이고; A가 발릴, 이소루실 또는 2-3차부틸글리실이고; B가 N-메틸발릴, 1-이소루실 또는 2-3차부틸글리실이고; D가 프롤릴, 티아졸리디닐-4-카르보닐 또는 3,4-데히드로프롤릴이고; E가 프롤릴, 티아졸리디닐-4-카르보닐, 호모프롤릴, 3,4-데히드로프롤릴 또는 히드록시프롤릴이고; K가 화학식 R5-N-R6을 갖는 치환되거나 비치환된 아미노 부분인 화학식 (I)의 화합물을 사용한다.Compounds of formula (I) are described in detail above. In certain embodiments, the process of the invention is a compound of formula (I), wherein R 1 and R 2 are each methyl or ethyl; X is isopropyl, secondary butyl or tertiary butyl; s is 1; t and u are each 0; A is valeryl, isoleucyl or 2-3 tertiary butyl glycyl; B is N-methylvalyl, 1-isosilyl or 2-3 tert-butylglycyl; D is prolyl, thiazolidinyl-4-carbonyl or 3,4-dehydroprolyl; E is prolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; Use is a compound of formula (I) wherein K is a substituted or unsubstituted amino moiety having the formula R 5 -NR 6 .
또 다른 구체예에 있어서, 본 발명의 방법은 화학식 (I)의 화합물로서, R1및 R2가 각각 메틸 또는 에틸이고; X가 이소프로필, 2차 부틸 또는 3차 부틸이고; s가 1이고; t 및 u가 각각 0이고; A가 발릴, 이소루실 또는 2-3차부틸글리실이고; B가 N-메틸발릴, 1-이소루실 또는 2-3차부틸글리실이고; D가 프롤릴, 티아졸리디닐-4-카르보닐 또는 3,4-데히드로프롤릴이고; E가 프롤릴, 티아졸리디닐-4-카르보닐, 호모프롤릴, 3,4-데히드로프롤릴 또는 히드록시프롤릴이고; K가 화학식 R5-N-R6을 갖는 치환된 아미노 부분이며, 여기서, R5는 수소 또는 C1-C4알콕시이고, R6는 예를 들어 하기 1가 라디칼로 표현되는 C1-C12직쇄 또는 측쇄 히드록시알킬 그룹인 화학식 (I)의 화합물을 사용한다:In another embodiment, the process of the invention is a compound of formula (I), wherein R 1 and R 2 are each methyl or ethyl; X is isopropyl, secondary butyl or tertiary butyl; s is 1; t and u are each 0; A is valeryl, isoleucyl or 2-3 tertiary butyl glycyl; B is N-methylvalyl, 1-isosilyl or 2-3 tert-butylglycyl; D is prolyl, thiazolidinyl-4-carbonyl or 3,4-dehydroprolyl; E is prolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; K is a substituted amino moiety having the formula R 5 -NR 6 , wherein R 5 is hydrogen or C 1 -C 4 alkoxy and R 6 is for example a C 1 -C 12 straight chain represented by the following monovalent radicals: Or use a compound of formula (I) which is a branched hydroxyalkyl group:
3-히드록시-1,1-디메틸프로필로서 또한 명명되는 -C(CH3)2-CH2-CH2-OH;-C (CH 3 ) 2 -CH 2 -CH 2 -OH, also referred to as 3-hydroxy-1,1-dimethylpropyl;
3차 부틸로서 또한 명명되는 -C(CH3)3;-C (CH 3 ) 3 , also named as tertiary butyl;
1,1-디메틸프로필로서 또한 명명되는;Also named as 1,1-dimethylpropyl ;
1-메틸-1-에틸프로필로서 또한 명명되는;Also named as 1-methyl-1-ethylpropyl ;
(S)- 또는 (R)-1-메틸-2,2-디메틸-프로필로서 또한 명명되는;Also named as (S)-or (R) -1-methyl-2,2-dimethyl-propyl ;
(S)- 또는 (R)-1-에틸-2-메틸프로필로서 또한 명명되는;Also named as (S)-or (R) -1-ethyl-2-methylpropyl ;
1-이소프로필-2-메틸-프로필로서 또한 명명되는; 또는Also named as 1-isopropyl-2-methyl-propyl ; or
1,1-디메틸-2-메틸프로필로서 또한 명명되는 -C(CH3)2-CH(CH3)2;-C (CH 3 ) 2 -CH (CH 3 ) 2 , also named as 1,1-dimethyl-2-methylpropyl;
이소프로필로서 또한 명명되는 -CH(CH3)2;-CH (CH 3 ) 2 , also named as isopropyl;
2차 부틸 [(S) 또는 (R)]로서 또한 명명되는 -CH(CH3)CH2CH3; 또는-CH (CH 3 ) CH 2 CH 3 , also referred to as secondary butyl [(S) or (R)]; or
1,2-디메틸프로필로서 또한 명명되는 -CH(CH3)CH(CH3)2.-CH (CH 3 ) CH (CH 3 ) 2 , also named as 1,2-dimethylpropyl.
또 다른 구체예에 있어서, 본 발명의 방법은 화학식 (I)의 화합물로서, R1및 R2가 각각 메틸 또는 에틸이고; X가 이소프로필, 2차 부틸 또는 3차 부틸이고; s가 1이고; t 및 u가 각각 0이고; A가 발릴, 이소루실 또는 2-3차부틸글리실이고; B가 N-메틸발릴, 1-이소루실 또는 2-3차부틸글리실이고; D가 프롤릴, 티아졸리디닐-4-카르보닐, 3,4-데히드로프롤릴이고; E가 프롤릴, 티아졸리디닐-4-카르보닐, 호모프롤릴, 3,4-데히드로프롤릴 또는 히드록시프롤릴이고; K가 화학식 R5-N-R6을 갖는 치환된 아미노 부분이며, 여기서, R5은 수소 또는 C1-C4알콕시이고, R6은 1가 라디칼, 예를 들어 C3-C10시클로알킬 그룹 (예를 들어, 시클로부틸, 시클로펜틸, 시클로헥실, 1-메틸시클로펜틸, 1-메틸시클로헥실 또는 비시클로[3.3.0]옥타-1-일); (1)- 또는 (2)-아다만틸 그룹; v가 1인 (CH2)v-펜틸 또는 α,α-디메틸벤질인 화학식 (I)의 화합물을 사용한다.In another embodiment, the process of the invention is a compound of formula (I), wherein R 1 and R 2 are each methyl or ethyl; X is isopropyl, secondary butyl or tertiary butyl; s is 1; t and u are each 0; A is valeryl, isoleucyl or 2-3 tertiary butyl glycyl; B is N-methylvalyl, 1-isosilyl or 2-3 tert-butylglycyl; D is prolyl, thiazolidinyl-4-carbonyl, 3,4-dehydroprolyl; E is prolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; K is a substituted amino moiety having the formula R 5 -NR 6 , wherein R 5 is hydrogen or C 1 -C 4 alkoxy and R 6 is a monovalent radical such as a C 3 -C 10 cycloalkyl group ( For example cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclopentyl, 1-methylcyclohexyl or bicyclo [3.3.0] octa-1-yl); (1)-or (2) -adamantyl groups; Use is made of compounds of formula (I) wherein v is (CH 2 ) v-pentyl or α, α-dimethylbenzyl.
또 다른 구체예에 있어서, 본 발명의 방법은 화학식 (I)의 화합물로서, R1및 R2이 각각 메틸이고; X가 이소프로필이고; s가 1이고; t 및 u가 각각 0이고; A가 발릴이고; B가 N-메틸발릴이고; D가 프롤릴이고; E가 프롤릴이고; K가 화학식 R5-N-R6을 갖는 치환된 아미노 부분이며, 여기서, R5은 벤질이고, R6은 수소인 화학식 (I)의 화합물을 사용한다. 이 화합물은 도면에 도시된 화합물 (xvii)에 상응한다. 화학식 (I)의 화합물 (xvii)을 파클리택셀과 조합하여 사용한 결과를 표 1 내지 4에 나타내었다.In another embodiment, the process of the invention is a compound of formula (I), wherein R 1 and R 2 are each methyl; X is isopropyl; s is 1; t and u are each 0; A is valeryl; B is N-methylvalyl; D is prolyl; E is prolyl; K is a substituted amino moiety having the formula R 5 -NR 6 , wherein R 5 is benzyl and R 6 is hydrogen. This compound corresponds to compound (xvii) shown in the figure. The results of using compound (xvii) of formula (I) in combination with paclitaxel are shown in Tables 1-4.
합성 방법Synthetic Method
화학식 (I)의 화합물은 공지된 펩티드 합성 방법, 예를 들어 본원에 기재된 방법 및 본원에 참고문헌으로 인용되어 있는 1995년 6월 7일자 출원된 미국 특허 출원 제 08/470,453호에 기재된 방법에 의해 제조될 수 있다. 펩티드는 개개의 아미노산으로 순차 어셈블링되거나 적당한 작은 펩티드 단편을 결합시킴으로써 어셈블링될 수 있다. 순차 어셈블리의 경우, 펩티드 사슬은 C 말단에서 출발하여 단계 마다 하나의 아미노산씩 단계적으로 연장된다. 단편 결합의 경우, 길이가 상이한 단편이 함께 결합될 수 있고, 단편은 아미노산으로부터의 순차 어셈블리 또는 여전히 짧은 단편의 단편 결합에 의해 또한 수득될 수 있다.Compounds of formula (I) may be prepared by known peptide synthesis methods, for example, the methods described herein and the methods described in US patent application Ser. No. 08 / 470,453, filed June 7, 1995, which is incorporated herein by reference. Can be prepared. Peptides can be assembled sequentially into individual amino acids or by assembling appropriate small peptide fragments. For sequential assembly, the peptide chain extends step by step, starting at the C terminus, one amino acid per step. In the case of fragment bonding, fragments of different lengths may be joined together, and the fragments may also be obtained by sequential assembly from amino acids or by fragment bonding of still short fragments.
순차 어셈블리 및 단편 결합 둘 모두에 있어서, 아미드 결합을 형성시킴으로써 단위들을 결합시킬 필요가 있으며, 이는 다양한 효소적 및 화학적 방법에 의해 달성될 수 있다. 펩티드 아미드 결합의 형성을 위해 본원에 기재된 방법은 비펩티드 아미드 결합의 형성을 위해 또한 적합하다.In both sequential assembly and fragment bonding, it is necessary to join the units by forming amide bonds, which can be achieved by various enzymatic and chemical methods. The methods described herein for the formation of peptide amide bonds are also suitable for the formation of nonpeptide amide bonds.
아미드 결합을 형성시키기 위한 화학적 방법은 펩티드 화학에 관한 표준 문헌에 상세히 기재되어 있으며, 이들 문헌으로는, 뮐러(Muller)의 문헌[Methoden der organischen Chemie Vol. XV/2, 1-364, Thieme Verlag, Stuttgart, (1974)]; 스튜어트(Stewart)와 영(Young)의 문헌[Solid Phase Peptide Synthesis, 31-34 and 71-82, Pierce Chemical Company, Rockford, IL (1984); 보단츠키(Bodanszky) 등의 문헌[Peptide Synthesis, 85-128, John Wiley & Sons, New York, (1976); Practice of Peptide Synthesis, M. Bodansky, A. Bodansky, Springer-Verlag, 1994] 및 펩티드 화학에 관한 기타 표준 문헌이 있다. 바람직한 방법으로는 아지드법, 대칭 및 혼합된 무수물법, 원위치 생성되거나 예비형성된 활성 에스테르의 사용, 아미노산의 우레탄 보호된 N-카르복시 무수물의 사용, 및 결합 시제, 예를 들어 디시클로헥실카르보디이미드 (DCC), 디이소프로필카르보디이미드 (DIC), 1-에톡시카르보닐-2-에톡시-1,2-디히드로퀴놀린 (EEDQ), 피발로일 클로라이드, 1-에틸-3-(3-디메틸아미노프로필) 카르보디이미드 히드로클로라이드 (EDCI), n-프로판-포스폰산 무수물 (PPA), N,N-비스(2-옥소-3-옥사졸리디닐)아미도 포스포릴 클로라이드 (BOP-C1), 브로모-트리스-피롤리디노포스포늄 헥사플루오로포스페이트 (PyBrop), 디페닐포스포릴 아지드 (DPPA), 카스트로 시제 (BOP, PyBop), O-벤조트리아졸릴-N,N,N',N'-테트라메틸우로늄 염 (HBTU), O-아자벤조트리아졸릴-N,N,N',N'-테트라메틸우로늄 염 (TATU), 디에틸포스포릴 시아나이드 (DEPCN), 2,5-디페닐-2,3-디히드로-3-옥소-4-히드로시티오펜 디옥사이드 (스테글리히 시제; HOTDO) 및 1,1'-카르보닐디이미다졸 (CDI)를 사용하는 아미드 결합의 형성이 있다. 결합 시제는 단독으로 또는 첨가제, 예를 들어 N,N-디메틸-4-아미노피리미딘 (DMAP), N-히드록시-벤조트리아졸 (HOBt), N-히드록시벤조트리아진 (HOOBt), N-히드록시숙신이미드 (HOSu) 또는 2-히드록시피리딘과 조합된 형태로 사용될 수 있다.Chemical methods for forming amide bonds are described in detail in the standard literature on peptide chemistry, which are described by Muller in Methode der organischen Chemie Vol. XV / 2, 1-364, Thieme Verlag, Stuttgart, (1974); Stewart and Young, Solid Phase Peptide Synthesis, 31-34 and 71-82, Pierce Chemical Company, Rockford, IL (1984); Bodanszky et al., Peptide Synthesis, 85-128, John Wiley & Sons, New York, (1976); Practice of Peptide Synthesis, M. Bodansky, A. Bodansky, Springer-Verlag, 1994] and other standard literature on peptide chemistry. Preferred methods include the azide method, the symmetrical and mixed anhydride method, the use of in situ generated or preformed active esters, the use of urethane protected N-carboxy anhydrides of amino acids, and binding reagents such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), pivaloyl chloride, 1-ethyl-3- (3 -Dimethylaminopropyl) carbodiimide hydrochloride (EDCI), n-propane-phosphonic anhydride (PPA), N, N-bis (2-oxo-3-oxazolidinyl) amido phosphoryl chloride (BOP-C1 ), Bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop), diphenylphosphoryl azide (DPPA), castro reagent (BOP, PyBop), O-benzotriazolyl-N, N, N ' , N'-tetramethyluronium salt (HBTU), O-azabenzotriazolyl-N, N, N ', N'-tetramethyluronium salt (TATU), die Ylphosphoryl cyanide (DEPCN), 2,5-diphenyl-2,3-dihydro-3-oxo-4-hydrocithiophene dioxide (Steglich reagent; HOTDO) and 1,1'-carbonyldi There is the formation of amide bonds using imidazole (CDI). Binding reagents alone or as additives, for example N, N-dimethyl-4-aminopyrimidine (DMAP), N-hydroxy-benzotriazole (HOBt), N-hydroxybenzotriazine (HOOBt), N It can be used in the form combined with -hydroxysuccinimide (HOSu) or 2-hydroxypyridine.
보호기의 사용은 효소적 펩티드 합성에서는 불필요한 것이 일반적이라고 하더라도, 아미드 결합의 형성에 관여하지 않는 반응성 그룹의 가역적 보호는 화학적 합성에서의 두 반응물 모두에 대해 필요하다. 화학적 펩티드 합성에 전형적으로 사용되는 3가지 통상적인 보호기 그룹 기법은 다음과 같다: 벤질옥시카르보닐 (Z), t-부톡시카르보닐 (Boc) 및 9-플루오레닐메톡시카르보닐 (Fmoc) 기법. 각각의 경우에서 사슬 연장 단위의 α-아미노 그룹에 있는 보호기가 확인된다. 아미노산 보호기는 뮐러(Muller)의 문헌[Methoden der organischen Chemie Vol. XV/1, pp 20-906, Thieme Verlag, Stutgart (1974)]에 상세히 기술되어 있다.Although the use of protecting groups is generally unnecessary in enzymatic peptide synthesis, reversible protection of reactive groups that are not involved in the formation of amide bonds is required for both reactants in chemical synthesis. Three conventional protecting group techniques typically used for chemical peptide synthesis are: benzyloxycarbonyl (Z), t-butoxycarbonyl (Boc) and 9-fluorenylmethoxycarbonyl (Fmoc) technique . In each case a protecting group in the α-amino group of the chain extension unit is identified. Amino acid protecting groups are described in Muller, Methoden der organischen Chemie Vol. XV / 1, pp 20-906, Thieme Verlag, Stutgart (1974).
펩티드 사슬을 어셈블링하기 위해 사용되는 단위는 용액 중, 현탁액 중 또는 메리필드(Merrifield)의 문헌[J. Amer. Chem. Soc. 85 (1963) 2149]에 기재된 방법과 유사한 방법에 의해 반응할 수 있다. 한 가지 방법에 있어서, 펩티드는 순차 어셈블링되거나, Z, Boc 또는 Fmoc 보호기 기법을, 불용성 중합체 지지체(이하 수지로서 또한 명명됨)에 결합되는 메리필드 기법에서의 반응물 중의 하나와 함께 사용하는 단편 결합에 의해 어셈블링된다. 이것은 Boc 또는 Fmoc 보호기 기법을, C 말단에서 불용성 수지 입자에 공유결합되는 증가하는 펩티드 사슬과 함께 사용하여 중합체 지지체 상에서 펩티드를 순차 어셈블링시키는 것을 수반하는 것이 전형적이다. 이 방법에 의해 시제와 부산물이 여과에 의해 제거됨으로써, 중간생성물을 재결정화시킬 필요가 없게된다.The units used to assemble the peptide chains are in solution, in suspension or in Merrifield, J. Amer. Chem. Soc. 85 (1963) 2149 can be reacted by a method analogous to that described. In one method, the peptide is sequentially assembled, or a fragment bond using the Z, Boc or Fmoc protecting group technique with one of the reactants in the Merrifield technique, which is bound to an insoluble polymer support (hereinafter also referred to as resin). Assembled by This typically involves sequential assembly of the peptides on the polymer support using Boc or Fmoc protecting group techniques with increasing peptide chains covalently bonded to the insoluble resin particles at the C terminus. In this way, the reagents and by-products are removed by filtration, eliminating the need to recrystallize the intermediate.
보호된 아미노산은 사용되는 용매 중에서 틀림없이 불용성이며, 여과될 수 있는 안정한 물리적 형태를 갖는 임의의 적당한 중합체에 결합될 수 있다. 중합체는 제 1 보호된 아미노산이 공유결합될 수 있는 작용기를 함유해야 한다. 다수의 중합체, 예를 들어 셀룰로오스, 폴리비닐 알코올, 폴리메타크릴레이트, 술폰화된 폴리스티렌, 클로로메틸화된 스티렌/디비닐벤젠 공중합체 (Merrifield resin), 4-메틸벤즈히드릴아민 수지 (MBHA-resin), 페닐아세트아미도메틸 수지 (Pam-resin), p-벤질옥시-벤질-알코올-수지, 벤즈히드릴-아민-수지 (BHA-resin), 브레이폴(Breipohl) 등의 문헌[Tetrahedron Letters 28 (1987) 565]에 기재된 수지인 4-(히드록시메틸)-벤조일-옥시메틸-수지 (BACHEM에 의해 공급됨), 4-(2,4-디메톡시페닐아미노메틸)페녹시 수지 (Novabiochem에 의해 공급됨) 또는 o-클로로트리틸-수지 (Biohellas에 의해 공급됨)가 이를 위해 적당하다.Protected amino acids are certainly insoluble in the solvents used and can be bound to any suitable polymer having a stable physical form that can be filtered. The polymer should contain a functional group to which the first protected amino acid can be covalently bonded. Many polymers such as cellulose, polyvinyl alcohol, polymethacrylates, sulfonated polystyrenes, chloromethylated styrene / divinylbenzene copolymers, 4-methylbenzhydrylamine resins (MBHA-resin ), Phenylacetamidomethyl resin (Pam-resin), p-benzyloxy-benzyl-alcohol-resin, benzhydryl-amine-resin (BHA-resin), Breipohl et al., Tetrahedron Letters 28 (1987) 565, 4- (hydroxymethyl) -benzoyl-oxymethyl-resin (supplied by BACHEM), 4- (2,4-dimethoxyphenylaminomethyl) phenoxy resin (Novabiochem Supplied) or o-chlorotrityl-resin (supplied by Biohellas) is suitable for this.
펩티드 합성에 적당한 용매로는 반응 조건하에 비활성인 용매, 예를 들어 물, N,N-디메틸포름아미드 (DMF), 디메틸 술폭사이드 (DMSO), 아세토니트릴, 디클로로메탄 (DCM), 1,4-디옥산, 테트라히드로푸란 (THF), N-메틸-2-피롤리돈 (NMP) 및 이들 용매의 혼합물이 있다.Suitable solvents for peptide synthesis include solvents that are inert under the reaction conditions, such as water, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dichloromethane (DCM), 1,4- Dioxane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP) and mixtures of these solvents.
중합체 지지체 상에서의 펩티드 합성은, 사용되는 아미노산 유도체 및 출발물질이 가용성인 적당한 비활성 유기 용매 중에서 수행될 수 있다. 특히 유용한 용매로는, 이들의 수지 팽윤 특성으로 인해, 예를 들어, DMF, DCM, NMP, 아세토니트릴, DMSO 및 이들의 혼합물이 있다.Peptide synthesis on the polymer support can be carried out in a suitable inert organic solvent in which the amino acid derivatives and starting materials used are soluble. Particularly useful solvents are, for example, DMF, DCM, NMP, acetonitrile, DMSO and mixtures thereof due to their resin swelling properties.
합성 후, 펩티드는 중합체 지지체로부터 분리된다 (분해된다고 보통 일컬어짐). 이 분해가 수행되는 조건은 펩티드 합성 분야에 널리 공지되어 있고, 사용되는 수지의 타입에 부분적으로 좌우된다. 가장 보편적으로 사용되는 분해 반응은 산 또는 팔라듐 촉매화되며, 산 촉매화된 분해는 예를 들어, 액체 무수 불화 수소, 무수 트리플루오로메탄술폰산, 및 아세트산/디클로로메탄/트리플루오로에탄올 혼합물 중에서 수행된다. 팔라듐 촉매화된 분해는 약염기, 예를 들어 모르폴린의 존재하에 THF 또는 THF-DCM-혼합물 중에서 수행될 수 있다. 특정 보호기는 이들 조건하에 또한 분해된다.After synthesis, the peptide is separated from the polymer support (commonly referred to as degraded). The conditions under which this degradation is carried out are well known in the art of peptide synthesis and depend in part on the type of resin used. The most commonly used decomposition reactions are acid or palladium catalyzed, acid catalyzed decompositions are carried out, for example, in liquid anhydrous hydrogen fluoride, trifluoromethanesulfonic anhydride, and acetic acid / dichloromethane / trifluoroethanol mixtures. do. Palladium catalyzed decomposition can be carried out in THF or THF-DCM-mixtures in the presence of a weak base, for example morpholine. Certain protecting groups also decompose under these conditions.
펩티드의 부분적 탈보호는 특정 유도체화 반응 전에 또한 필요할 수 있다. 예를 들어, N 말단에서 디알킬화된 펩티드는, 적당한 N,N-디알킬아미노산을 용액 중의 펩티드 또는 중합체 지지체 상의 펩티드에 결합시키거나, 수지 결합된 펩티드를 DMF/1% 아세트산 중에서 NaCNBH3및 적당한 알데히드에 의해 환원성 알킬화시키거나, 펩티드를 알데히드 또는 케톤 및 Pd/C의 존재하에 용액 중에서 펩티드를 수소화시킴으로써 제조될 수 있다.Partial deprotection of peptides may also be necessary before certain derivatization reactions. For example, a peptide that is dialkylated at the N-terminus may be a suitable N, N-dialkylamino acid bound to a peptide in solution or a peptide on a polymer support, or the resin-bound peptide may be reacted with NaCNBH 3 and appropriate in DMF / 1% acetic acid. Reductive alkylation with aldehydes or peptides can be prepared by hydrogenating the peptides in solution in the presence of aldehydes or ketones and Pd / C.
다양한 합성 아미노산 뿐만 아니라 본원에 기재된 다양한 비아미노산 부분은 상업적 공급원으로부터 수득되거나, 통상적인 물질로부터 당 분야에 공지된 방법을 사용하여 합성될 수 있다. 예를 들어, R1및 R2부분을 갖는 아미노산 빌딩 블록은 이. 부엔쉬, 후벤 베일 (E. Wuensch, Huben Weyl)의 문헌[Methoden der organischen Chemie Vol. XV/1, p. 306, Thieme Verlag, Stuttgart (1974)] 및 여기에 인용된 문헌에 기재된 방법에 따라 제조될 수 있다. 감마- 또는 델타-락탐 브릿지를 갖는 펩티드는 적당한 락탐 브릿지된 디펩티드 단위 (R. Freidinger, J. Org. Chem. (1982) 104-109)를 펩티드 사슬에 혼입시킴으로써 제조될 수 있다. 티아졸, 옥사졸, 티아졸린 또는 옥사졸린 함유 디펩티드 빌딩 블록은, 적당한 디펩티드 단위 (P. Jouin et al., Tetrahedron Letters (1992), pp. 2087-2810; P. Wipf et al., Tetrahedon Letters (1992), pp. 907-910; W.R. Tully, J. Med. Chem. (1991), p 2065; Synthesis (1987), p 235)를 펩티드 사슬에 혼입시킴으로써 제조될 수 있다.Various synthetic amino acids as well as various non-amino acid moieties described herein can be obtained from commercial sources or synthesized from conventional materials using methods known in the art. For example, amino acid building blocks having R 1 and R 2 moieties are E. coli. E. Wuensch, Huben Weyl, Methods der organischen Chemie Vol. XV / 1, p. 306, Thieme Verlag, Stuttgart (1974) and the literature cited therein. Peptides having gamma- or delta-lactam bridges can be prepared by incorporating suitable lactam bridged dipeptide units (R. Freidinger, J. Org. Chem. (1982) 104-109) into the peptide chain. Thiazole, oxazole, thiazolin or oxazoline containing dipeptide building blocks may be prepared by using suitable dipeptide units (P. Jouin et al., Tetrahedron Letters (1992), pp. 2087-2810; P. Wipf et al., Tetrahedon Letters (1992), pp. 907-910; WR Tully, J. Med. Chem. (1991), p 2065; Synthesis (1987), p 235) can be prepared by incorporation into peptide chains.
하기 과정은 화학식 (I)의 화합물의 제조에 유용한 방법을 예시하기 위해 의도된다. 적절한 경우, 아미노산은 공지된 3문자 코드를 사용하여 약기된다. 사용된 기타 용어에 대한 의미는 다음과 같다: Me2Val = N,N-디메틸발린, MeVal = N-메틸발린, TFA = 트리플루오로아세트산, Ac = 아세트산, Bu = 부틸, Et = 에틸, Me = 메틸, Bzl = 벤질, Nal = 3-나프틸알라닌, Cha = 3-시클로헥실알라닌, Npg = 네오펜틸 글리신, Abu = 2-아미노 부티릴, Dab = 2,4-디아미노부티릴, iPr = 이소프로필.The following procedure is intended to illustrate the methods useful for the preparation of compounds of formula (I). Where appropriate, amino acids are abbreviated using known three letter codes. The meanings for the other terms used are as follows: Me 2 Val = N, N-dimethylvaline, MeVal = N-methylvaline, TFA = trifluoroacetic acid, Ac = acetic acid, Bu = butyl, Et = ethyl, Me = Methyl, Bzl = benzyl, Nal = 3-naphthylalanine, Cha = 3-cyclohexylalanine, Npg = neopentyl glycine, Abu = 2-amino butyryl, Dab = 2,4-diaminobutyryl, iPr = Isopropyl.
일반적 합성 과정General synthesis process
I. 본 발명의 화학식 (I)의 화합물은 전술된 표준 Z 및 Boc 방법을 사용하는 통상적인 용액 합성법 또는 어플라이드 바이오시스템스 (APPLIED BIOSYSTEMS)에 의해 공급되는 전자동 모델 431A 합성기에서 고체상 합성하는 표준 방법에 의해 합성된다. 장치는 Boc 및 Fmoc 보호기 기법에 대해 상이한 합성 사이클을 이용한다.I. Compounds of formula (I) of the present invention are prepared by conventional solution synthesis using the standard Z and Boc methods described above or by standard methods for solid phase synthesis in fully automatic model 431A synthesizers supplied by APPLIED BIOSYSTEMS. Are synthesized. The device uses different synthesis cycles for the Boc and Fmoc protecting group techniques.
고체상 합성의 경우, N,N-디알킬펜타 또는 헥사펩티드산은 고체 지지체로부터 유리되고, 용액 중에서 상응하는 C 말단 아민과 추가로 결합된다. BOP-C1 및 PyBrop를 시제로서 사용하여 N-메틸아미노산 다음에 위치하는 아미노산을 결합시켰다. N 말단의 환원성 알킬화를 위해, 펩티드-수지를 N 말단에서 탈보호시킨 후, DMF/1% 아세트산 중에서 3배 몰 과량의 알데히드 또는 케톤과 반응시키면서, NaCNBH33 당량을 첨가시켰다. 반응이 완결된 후 (네거티브 카이저(Kaiser) 테스트), 수지를 물, 이소프로판올, DMF 및 디클로로메탄으로 수 회 세척시켰다.For solid phase synthesis, N, N-dialkylpenta or hexapeptide acid is released from the solid support and further bound with the corresponding C terminal amine in solution. BOP-C1 and PyBrop were used as reagents to bind amino acids located after N-methylamino acids. For reductive alkylation at the N terminus, the peptide-resin was deprotected at the N terminus, followed by addition of 3 equivalents of NaCNBH 3 while reacting with a 3-fold molar excess of aldehyde or ketone in DMF / 1% acetic acid. After the reaction was complete (negative Kaiser test), the resin was washed several times with water, isopropanol, DMF and dichloromethane.
용액 합성의 경우, Boc 보호된 아미노산 NCA (N-3차부틸옥시카르보닐-아미노산-N-카르복시-무수물), Z 보호된 아미노산 NCA (N-벤질옥시카르보닐-아미노산-N-카르복시-무수물) 또는 피발로일클로라이드를 각각 응축제로서 사용하는 것이 N-메틸아미노산 다음에 위치하는 아미노산을 결합시키기 위해 가장 유리하다. N 말단의 환원성 알킬화는 예를 들어, NaCNBH 또는 수소, Pd/C를 사용하여 N 말단 탈보호된 펩티드 또는 아미노산을 상응하는 알데히드 또는 케톤과 반응시킴으로써 달서오딜 수 있다.For solution synthesis, Boc protected amino acid NCA (N-tertbutyloxycarbonyl-amino acid-N-carboxy-anhydride), Z protected amino acid NCA (N-benzyloxycarbonyl-amino acid-N-carboxy-anhydride) Or the use of pivaloylchloride as the condensing agent, respectively, is most advantageous for binding the amino acids located after the N-methylamino acids. N-terminal reductive alkylation can be sweetened by, for example, reacting an N-terminal deprotected peptide or amino acid with the corresponding aldehyde or ketone using NaCNBH or hydrogen, Pd / C.
a) Boc 보호기 기법을 위한 합성 사이클a) Synthesis Cycle for Boc Protector Technique
1. DCM 중의 30% 트리플루오로아세트산 1 x 3 분1. 30% trifluoroacetic acid in DCM 1 x 3 minutes
2. DCM 중의 50% 트리플루오로아세트산 1 x 1 분2. 1 x 1 min 50% trifluoroacetic acid in DCM
3. DCM 세척3. DCM washing
4. DCM 중의 5% 디이소프로필에틸아민 5 x 1 분4. 5% diisopropylethylamine in DCM 5 x 1 min
5. NMP 중의 5% 디이소프로필에틸아민 1 x 1 분5. 1 x 1 min 5% diisopropylethylamine in NMP
6. NMP 세척 5 x 1 분6. NMP wash 5 x 1 min
7. 예비활성화된 보호된 아미노산 (NMP/DCM 중의 DCC와 HOBt 1 당량)의 첨가; 펩티드 결합 (첫 번째 부분) 1 x 30 분7. addition of preactivated protected amino acids (1 equivalent of DCC and HOBt in NMP / DCM); Peptide Bond (First Part) 1 x 30 Minutes
8. DMSO 20 부피%를 함유할 때까지 반응 혼합물에8. Add to the reaction mixture until it contains 20% by volume DMSO.
DMSO를 첨가; 펩티드 결합 (두 번째 부분) 1 x 16 분Adding DMSO; Peptide Bond (second part) 1 x 16 min
9. 반응 혼합물에 디이소프로필에틸아민9. Diisopropylethylamine in the reaction mixture
3.8 당량을 첨가; 펩티드 결합 (세 번째 부분) 1 x 7 분Add 3.8 equivalents; Peptide Bond (third part) 1 x 7 min
10. DCM 세척 3 x 1 분10. DCM wash 3 x 1 min
11. 전환이 불충분한 경우,11. If conversion is insufficient,
결합 반응을 반복 (6번으로 되돌아감)Repeat the binding reaction (return to step 6)
12. DCM 중의 10% 아세트산 무수물,12. 10% acetic anhydride in DCM,
5% 디이소프로필에티아민 1 x 2 분5% diisopropylethhiamine 1 x 2 minutes
13. DCM 중의 10% 아세트산 무수물 1 x 4 분13. 10% acetic anhydride in DCM 1 x 4 min
14. DCM 세척 4 x 1 분14. DCM wash 4 x 1 min
15. 1번으로 되돌아감.15. Return to number 1.
BOP-C1 및 PyBrop를 시제로서 사용하여 N-메틸아미노산 다음에 위치하는 아미노산을 결합시켰다. 반응 시간을 상응하게 늘렸다. 용액 합성의 경우, Boc 보호된 아미노산 NCA (N-3차부틸옥시카르보닐-아미노산-N-카르복시-무수물) 또는 Z 보호된 아미노산 NCA (N-벤질옥시카르보닐-아미노산-N-카르복시-무수물)을 각각 사용하는 것이 이 유형의 결합에 가장 유리하다.BOP-C1 and PyBrop were used as reagents to bind amino acids located after N-methylamino acids. The reaction time was correspondingly increased. For solution synthesis, Boc protected amino acid NCA (N-tertbutyloxycarbonyl-amino acid-N-carboxy-anhydride) or Z protected amino acid NCA (N-benzyloxycarbonyl-amino acid-N-carboxy-anhydride) It is most advantageous for this type of bonding to use respectively.
b) Fmoc 보호기 기법을 위한 합성 사이클:b) Synthesis cycle for Fmoc protecting group technique:
1. DMF 세척 1 x 1 분1. DMF wash 1 x 1 min
2. DMF 중의 20% 피페리딘 1 x 4 분2. 20% piperidine 1 x 4 min in DMF
3. DMF 중의 20% 피페리딘 1 x 16 분3. 20% piperidine 1 x 16 min in DMF
4. DMF 세척 5 x 1 분4. DMF wash 5 x 1 min
5. 예비활성화된 보호된 아미노산 (DMF 중의 TBTU 1 당량과 DIPEA 5 당량에 의한 활성화)의 첨가; 펩티드 결합 1 x 61 분5. addition of preactivated protected amino acids (activation by 1 equivalent of TBTU and 5 equivalents of DIPEA in DMF); Peptide Bond 1 x 61 Min
6. DMF 세척 3 x 1 분6. DMF wash 3 x 1 min
7. 전환이 불충분한 경우,7. If the conversion is insufficient,
결합 반응을 반복 (5번으로 되돌아감)Repeat the binding reaction (return to step 5)
8. DMF 중의 10% 아세트산 무수물 1 x 8 분8. 10% acetic anhydride in DMF 1 x 8 min
9. DMF 세척 3 x 1 분9. DMF wash 3 x 1 min
10. 2번으로 되돌아감.10. Return to step 2.
BOP-C1과 PyBrop를 시제로서 사용하여 N-메틸아미노산 다음에 위치하는 아미노산을 결합시켰다. 반응 시간을 상응하게 늘렸다.BOP-C1 and PyBrop were used as reagents to bind amino acids located after N-methylamino acids. The reaction time was correspondingly increased.
II. N 말단의 환원성 알킬화II. N-terminal reductive alkylation
상기 I. a) 또는 I. b)에서 제조된 펩티드-수지를 N 말단에서 탈보호시킨 후 (I. b)의 단계 2 내지 4 또는 I. a)의 단계 1 내지 6), DMF/1% 아세트산 중의 3배 몰 과량의 알데히드 또는 케톤과 반응시키면서 NaCNBH33 당량을 첨가시켰다. 반응이 완결된 후 (네거티브 카이저 테스트), 수지를 물, 이소프로판올, DMF 및 디클로로메탄으로 수 회 세척시켰다.Deprotection at the N terminus of the peptide-resin prepared in I. a) or I. b), followed by steps 2 to 4 of (I. b) or steps 1 to 6) of I. a), DMF / 1% NaCNBH 3 3 equivalents were added while reacting with a 3-fold molar excess of aldehyde or ketone in acetic acid. After the reaction was complete (negative Kaiser test), the resin was washed several times with water, isopropanol, DMF and dichloromethane.
III. I. a) 및 II 에서 수득된 펩티드-수지의 조작III. I. Manipulation of the Peptide-Resins Obtained in a) and II
펩티드-수지를 감압하에 건조시키고, 테플론(TEFLON) HF 장치 (페닌술라(PENINSULA)에 의해 공급됨)의 반응 용기로 옮겼다. 스캐빈저, 예를 들어 아니솔 (수지 1g 당 1㎖) 및 인돌 포르밀 그룹을 제거시키기 위한 티올의 트립토판 함유 펩티드의 경우, 예를 들어 에탄디티올 (수지 1g 당 0.5㎖)을 첨가한 후, 불화 수소 (수지 1g 당 10㎖) 중에서 응축시키면서 액체 N2로 냉각시켰다. 혼합물을 0℃로 가온시키고, 이 온도에서 45분간 교반시켰다. 그 후, 불화 수소를 감압하에 스트립핑시키고, 잔류물을 에틸 아세테이트로 세척하여, 남아있는 스캐빈저를 제거시켰다. 펩티드를 30% 아세트산으로 추출 및 여과시키고, 여액을 동결건조시켰다.The peptide-resin was dried under reduced pressure and transferred to the reaction vessel of a TEFLON HF apparatus (supplied by PENINSULA). For tryptophan containing peptides of scavenger, e.g. anisole (1 ml per gram of resin) and thiol to remove indole formyl groups, for example ethanedithiol (0.5 ml per gram of resin) And cooled with liquid N 2 while condensing in hydrogen fluoride (10 ml per 1 g of resin). The mixture was warmed to 0 ° C. and stirred at this temperature for 45 minutes. The hydrogen fluoride was then stripped under reduced pressure and the residue was washed with ethyl acetate to remove any remaining scavenger. Peptides were extracted and filtered with 30% acetic acid and the filtrate was lyophilized.
IV. I. b) 및 II에서 수득된 펩티드-수지의 조작IV. I. Operation of Peptide-Resins Obtained in b) and II
펩티드-수지를 감압하에 건조시킨 후, 아미노산 조성에 따라, 하기 분해 과정 중의 하나로 처리하였다 (참조: Wade, Tregear, Howard Florey Fmoc Workshop Manual, Melbourne 1985).The peptide-resin was dried under reduced pressure and then treated with one of the following degradation procedures, depending on the amino acid composition (Wade, Tregear, Howard Florey Fmoc Workshop Manual, Melbourne 1985).
분해 조건:Decomposition Condition:
적당한 TFA 혼합물 중의 펩티드-수지의 현탁액을 실온에서 지정 시간 동안 교반시킨 후, 수지를 여과시키고, TFA 및 DCM으로 세척시켰다. 여액 및 세척액을 농축시키고, 펩티드를, 디에틸 에테르를 첨가시킴으로써 침전시켰다. 얼음조에서 냉각시킨 후, 침전물을 여과시키고, 30% 아세트산 중에서 용해시키고, 동결건조시켰다.The suspension of peptide-resin in a suitable TFA mixture was stirred at room temperature for a designated time, after which the resin was filtered and washed with TFA and DCM. The filtrate and washes were concentrated and the peptide was precipitated by addition of diethyl ether. After cooling in an ice bath, the precipitate was filtered off, dissolved in 30% acetic acid and lyophilized.
V. o-클로로트리틸-수지 (바이오헬라스(Biohellas)에 의해 공급됨)가 사용되는 경우, 아세트산/트리플루오로에탄올/디클로로메탄 혼합물 (1:1:3) 중의 펩티드-수지의 현탁액을 실온에서 1시간 동안 교반시켰다. 그 후, 수지를 흡인에 의해 여과시키고, 분해 용액으로 철저히 세척시켰다. 조합된 여액을 진공중에서 농축시키고, 물로 처리시켰다. 침전된 고체를 여과 또는 원심분리에 의해 분리하고, 디에틸 에테르로 세척시키고, 감압하에 건조시켰다.V. When o-chlorotrityl-resin (supplied by Biohellas) is used, the suspension of peptide-resin in an acetic acid / trifluoroethanol / dichloromethane mixture (1: 1: 3) Stirred for 1 h. Thereafter, the resin was filtered by suction and washed thoroughly with a decomposition solution. The combined filtrates were concentrated in vacuo and treated with water. The precipitated solid was separated by filtration or centrifugation, washed with diethyl ether and dried under reduced pressure.
VI. 펩티드의 정제 및 특징화VI. Purification and Characterization of Peptides
정제를, 겔 크로마토그래피 (SEPHADEX G-10, G-15/10% HOAc, SEPHADEX LH20/MeOH), 중압력 크로마토그래피 (정지상: HD-SIL C-18, 20-45㎛, 100Å; 이동상: A가 0.1% TFA/MeOH이고, B가 0.1% TFA/물인 구배) 또는 제조 HPLC (정지상: 물 Delta-Pak C-18, 15㎛, 100Å; 이동상: A가 0.1% TFA/MeOH이고, B가 0.1% TFA/물인 구배)에 의해 수행하였다.Purification was carried out by gel chromatography (SEPHADEX G-10, G-15 / 10% HOAc, SEPHADEX LH20 / MeOH), medium pressure chromatography (still phase: HD-SIL C-18, 20-45 μm, 100 Hz; mobile phase: A Is 0.1% TFA / MeOH, B is 0.1% TFA / water) or preparative HPLC (still phase: Water Delta-Pak C-18, 15 μm, 100 μs; mobile phase: A is 0.1% TFA / MeOH, B is 0.1 Gradient with% TFA / water).
생성된 생성물의 순도를 분석 HPLC (정지상: 1002.1㎜ VYDAC C-18, 5l, 300Å; 이동상: 0.1% TFA로 완충된 아세토니트릴-물 구배, 40℃)에 의해 결정하였다.Purity of the resulting product was determined by analytical HPLC (still phase: 1002.1 mm VYDAC C-18, 5L, 300 cc; mobile phase: acetonitrile-water gradient buffered with 0.1% TFA, 40 ° C.).
특징화를 아미노산 분석 및 고속 원자 충격 질량 분광학에 의해 수행하였다.Characterization was performed by amino acid analysis and fast atomic bombard mass spectroscopy.
특정 합성 과정Specific synthesis process
실시예 1A: N,N-디메틸-Val-Val-N-메틸-Val-Pro-Pro-Val-Phe-NH2 Example 1A: N, N-Dimethyl-Val-Val-N-methyl-Val-Pro-Pro-Val-Phe-NH 2
배치 크기 0.84mmol에 상응하는 Fmoc-RINK-수지 1.98g (치환율: 0.46mmol/g)을 개개의 하기 물질 1.26mmol과 상기 I. b)에 기재된 바와 같이 반응시켰다:1.98 g of Fmoc-RINK-resin (substitution rate: 0.46 mmol / g), corresponding to a batch size of 0.84 mmol, were reacted with 1.26 mmol of the following material as described in I. b) above:
Fmoc-Phe-OHFmoc-Phe-OH
Fmoc-Val-OHFmoc-Val-OH
Fmoc-Pro-OHFmoc-Pro-OH
Fmoc-Pro-OHFmoc-Pro-OH
Fmoc-N-메틸-Val-OHFmoc-N-methyl-Val-OH
Fmoc-Val-OHFmoc-Val-OH
Fmoc-Val-OHFmoc-Val-OH
N-메틸 아미노산 다음에 위치하는 아미노산을 PyBrop을 결합 시제로서 사용하여 결합시켰다. 반복 합성 사이클을 완료한 후, 펩티드-수지를 N 말단 탈보호시키고 (I. b) 중의 단계 2 내지 4), 과정 II에서와 같이 포름알데히드 수용액과 추가로 반응시킨 후, 감압하에 건조시켰다. 생성된 수지를 과정 IV에서와 같이 TFA 분해로 처리하였다. 미정제 생성물 (590㎎)을 겔 여과 (SEPHADEX-LH-20)에 의해 정제시켰다. 수율은 295㎎ 이었다.An amino acid located after the N-methyl amino acid was bound using PyBrop as the binding reagent. After completion of the repeated synthesis cycle, the peptide-resin was N-terminal deprotected and further reacted with aqueous formaldehyde aqueous solution as in steps 2-4) in I. b), followed by drying under reduced pressure. The resulting resin was treated by TFA digestion as in process IV. The crude product (590 mg) was purified by gel filtration (SEPHADEX-LH-20). The yield was 295 mg.
실시예 1A:Example 1A:
실시예 1의 생성물을 통상적인 용액상 방법에 의해 제조할 수 있다. N,N-디메틸-Val-Val-N-메틸-Val-Pro-Pro-Val-Phe-NH2와 이것의 관련된 중간생성물의 합성 과정을 하기 기재하였다.The product of Example 1 can be prepared by conventional solution phase methods. The procedure for the synthesis of N, N-dimethyl-Val-Val-N-methyl-Val-Pro-Pro-Val-Phe-NH 2 and its related intermediates is described below.
a) Z-MeVal-Pro-OMea) Z-MeVal-Pro-OMe
Z-MeVal-OH 66.25g (250mmol)을 무수 디클로로메탄 250㎖ 중에 용해시켰다. 트리에틸아민 36.41㎖ (262.5mmol)을 첨가시킨 후, 반응 혼합물을 -25℃로 냉각시키고, 피발로일 클로라이드 32.37㎖ (262.5mmol)을 첨가시켰다. 2.5시간 동안 교반시킨 후, 0℃에서 트리에틸아민 36.41㎖ (262.5mmol)로 중화시킨 디클로로메탄 250㎖ 중의 H-Pro-OMe-HCl 41.89g (250mmol)을 반응 혼합물에 첨가시켰다. 교반을 -25℃에서 2시간 동안 계속 수행하고, 실온에서 밤새 수행하였다. 반응 혼합물을 디클로로메탄으로 희석시키고, NaHCO3포화 수용액 (3X), 물 (1X), 5% 시트르산 (3X) 및 NaCl 포화 용액으로 철저히 세척시켰다. 유기상을 황산나트륨으로 건조시키고, 여과시키고, 증발 건조시켰다. 잔류물 (91.24g)을 석유 에테르로 밤새 교반시키고, 여과시켰다. 생성물 62.3g을 수득하였다.66.25 g (250 mmol) of Z-MeVal-OH were dissolved in 250 mL of anhydrous dichloromethane. After addition of 36.41 mL (262.5 mmol) of triethylamine, the reaction mixture was cooled to -25 ° C and 32.37 mL (262.5 mmol) pivaloyl chloride were added. After stirring for 2.5 hours, 41.89 g (250 mmol) of H-Pro-OMe-HCl in 250 mL of dichloromethane neutralized with 36.41 mL (262.5 mmol) triethylamine at 0 ° C. was added to the reaction mixture. Stirring was continued for 2 h at −25 ° C. and overnight at rt. The reaction mixture was diluted with dichloromethane and washed thoroughly with saturated aqueous NaHCO 3 ( 3 ×), water (1 ×), 5% citric acid (3 ×) and saturated NaCl. The organic phase was dried over sodium sulphate, filtered and evaporated to dryness. The residue (91.24 g) was stirred overnight with petroleum ether and filtered. 62.3 g of product was obtained.
b) H-MeVal-Pro-OMeb) H-MeVal-Pro-OMe
Z-MeVal-Pro-OMe 48.9g (130mmol)을 메탄올 490㎖ 중에 용해시켰다. 진한 염산 10.9㎖ (130mmol)과 10% 팔라듐/숯 2.43g을 첨가시킨 후, 반응 혼합물을 수소화시켰다. 여과 및 증발 건조시켜서, 생성물 36.43g을 수득하였다.48.9 g (130 mmol) of Z-MeVal-Pro-OMe was dissolved in 490 mL of methanol. After addition of 10.9 mL (130 mmol) of concentrated hydrochloric acid and 2.43 g of 10% palladium / charcoal, the reaction mixture was hydrogenated. Filtration and evaporation to dryness yielded 36.43 g of product.
c) Z-Val-MeVal-Pro-OMec) Z-Val-MeVal-Pro-OMe
H-MeVal-Pro-OMe 18.1g (65mmol), Z-Val-N-카르복시무수물 21.6g (78mmol) 및 디이소프로필에틸아민 22.8㎖ (130mmol)을 DMF 110㎖ 중에서 40℃에서 2일간 교반시켰다. DMF를 증발시킨 후, 디클로로메탄을 첨가하고, 유기상을 NaHCO3포화 수용액 (3X), 물 (1X), 5% 시트르산 (3X) 및 NaCl 포화 수용액으로 세척시켰다. 유기상을 황산나트륨으로 건조시키고, 여과시키고, 증발 건조시켰다. 생성물 (29.3g)을 점성 오일로서 수득하였다.18.1 g (65 mmol) of H-MeVal-Pro-OMe, 21.6 g (78 mmol) of Z-Val-N-carboxy anhydride and 22.8 mL (130 mmol) of diisopropylethylamine were stirred in DMF 110 mL at 40 ° C. for 2 days. After evaporating DMF, dichloromethane was added and the organic phase was washed with saturated aqueous NaHCO 3 ( 3 ×), water (1 ×), 5% citric acid (3 ×) and saturated aqueous NaCl solution. The organic phase was dried over sodium sulphate, filtered and evaporated to dryness. Product (29.3 g) was obtained as a viscous oil.
d) H-Val-MeVal-Pro-OMed) H-Val-MeVal-Pro-OMe
Z-Val-MeVal-Pro-OMe 29.3g (61.6 mmol)을 메탄올 230㎖ 중에 용해시켰다. 10% 팔라듐/숯 1.15g을 첨가시킨 후, 반응 혼합물을 수소화시켰다. 여과 및 증발 건조시켜서, 생성물 21.96g을 수득하였다.29.3 g (61.6 mmol) of Z-Val-MeVal-Pro-OMe were dissolved in 230 mL of methanol. After addition of 1.15 g of 10% palladium / charcoal, the reaction mixture was hydrogenated. Filtration and evaporation to dryness yielded 21.96 g of product.
e) Z-Val-Val-MeVal-Pro-OMee) Z-Val-Val-MeVal-Pro-OMe
Z-Val-OH 15.29g (61mmol) 및 H-Val-MeVal-Pro-OMe 21.96g (61mmol)을 디클로로메탄 610㎖ 중에 용해시키고, 0℃로 냉각시켰다. N-메틸모르폴린 8.16mol (73.2mmol), HOBt 2.77g (20.3mmol) 및 EDCI 11.74g (61mmol)을 첨가시킨 후, 반응 혼합물을 실온에서 밤새 교반시키고, 디클로로메탄으로 희석시키고, NaHCO 포화 수용액 (3X), 물 (1X), 5% 시트르산 (3X) 및 NaCl 포화 수용액으로 철저히 세척시켰다. 유기상을 황산나트륨에서 건조시키고, 여과시키고, 증발 건조시켜서, 생성물 31.96g을 수득하였다.15.29 g (61 mmol) of Z-Val-OH and 21.96 g (61 mmol) of H-Val-MeVal-Pro-OMe were dissolved in 610 mL of dichloromethane and cooled to 0 ° C. After addition of 8.16 mol (73.2 mmol) of N-methylmorpholine, 2.77 g (20.3 mmol) of HOBt and 11.74 g (61 mmol) of EDCI, the reaction mixture was stirred overnight at room temperature, diluted with dichloromethane and saturated aqueous NaHCO solution ( 3X), water (1X), 5% citric acid (3X) and saturated aqueous NaCl solution. The organic phase was dried over sodium sulphate, filtered and evaporated to dryness to afford 31.96 g of product.
f) Z-Val-Val-MeVal-Pro-OHf) Z-Val-Val-MeVal-Pro-OH
Z-Val-Val-MeVal-Pro-OMe 31.96g (57mmol)을 메탄올 250㎖ 중에 용해시켰다. 1N LiOH 용액 102.6㎖을 첨가시키고, 혼합물을 실온에서 밤새 교반시켰다. 물 500㎖를 첨가시킨 후, 수성상을 에틸 아세테이트로 3회 세척하였다. 유기상을 황산나트륨으로 건조시키고, 여과시키고, 증발 건조시켜서, 원하는 생성물 30.62g을 백색 고체로서 수득하였다.31.96 g (57 mmol) of Z-Val-Val-MeVal-Pro-OMe were dissolved in 250 ml of methanol. 102.6 mL of 1N LiOH solution was added and the mixture was stirred at rt overnight. After addition of 500 ml of water, the aqueous phase was washed three times with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness to afford 30.62 g of the desired product as a white solid.
g) Z-Val-Val-MeVal-Pro-Pro-Val-Phe-NH2 g) Z-Val-Val-MeVal-Pro-Pro-Val-Phe-NH 2
Z-Val-Val-MeVal-Pro-OH 25g (43.3mmol) 및 H-Pro-Val-Phe-NH 15.59g (43.3mmol)을 무수 디클로로메탄 430㎖ 중에 현탁시켰다. 0℃로 냉각시킨 후, N-메틸모르폴린 5.81㎖ (52mmol), HOBt 1.97g (15mmol) 및 EDCI 8.33g (43.3mmol)을 첨가시키고, 반응 혼합물을 실온에서 밤새 교반시켰다. 용매를 증발시키고, 잔류물을 디클로로메탄 640㎖ 중에 용해시키고, NaHCO3포화 수용액 (4X), 물 (1X), 5% 시트르산 (3X) 및 NaCl 포화 용액으로 철저히 세척시켰다. 유기상을 황산나트륨으로 건조시키고, 여과시키고, 증발 건조시켜서, 생성물 33.04g을 수득하였다. 미정제 생성물을 20% MeOH/헥산을 사용하여 실리카겔 칼럼에서 크로마토그래피시켰다. 원하는 생성물 18.32g을 수득하였다.25 g (43.3 mmol) of Z-Val-Val-MeVal-Pro-OH and 15.59 g (43.3 mmol) of H-Pro-Val-Phe-NH were suspended in 430 mL of anhydrous dichloromethane. After cooling to 0 ° C., 5.81 ml (52 mmol) N-methylmorpholine, 1.97 g (15 mmol) HOBt and 8.33 g (43.3 mmol) EDCI were added and the reaction mixture was stirred at rt overnight. The solvent was evaporated and the residue was dissolved in 640 mL of dichloromethane and washed thoroughly with saturated aqueous NaHCO 3 (4 ×), water (1 ×), 5% citric acid (3 ×) and saturated NaCl solution. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness to give 33.04 g of product. The crude product was chromatographed on silica gel column with 20% MeOH / hexanes. 18.32 g of the desired product were obtained.
h) N,N-디메틸-Val-Val-MeVal-Pro-Pro-Val-Phe-NH2 h) N, N-dimethyl-Val-Val-MeVal-Pro-Pro-Val-Phe-NH 2
Z-Val-Val-MeVal-Pro-Pro-Val-Phe-NH218.32g을 메탄올 80㎖에 용해시켰다. 10% 팔라듐/탄소 0.4g을 질소 분위기하에 첨가하고, 반응 혼합물을 실온에서 4시간 동안 수소화시켰다. 37% 포름알데히드 수용액 6.22㎖ (81.24mmol)을 첨가시킨 후, 수소화를 5시간 동안 계속 수행하였다. 용매를 여과 및 증발시켜, 미정제 생성물 15.6g을 수득하였다. 펩티드를 물에 용해시키고, pH를 2로 조정하고, 수성상을 에틸 아세테이트로 3회 추출함으로써 추가 정제를 수행하였다. 그 후, 수성상을 pH 8 내지 9로 조정하고, 에틸 아세테이트로 4회 추출하였다. 유기상을 물로 세척시키고, 황산나트륨으로 건조시키고, 여과 및 증발시켜서, 정제된 생성물 11.3g을 백색 분말로서 수득하였다. 화합물을 고속 원자 충격 질량 분광학에 의해 특징화하였다 ([M+H]+= 797).18.32 g of Z-Val-Val-MeVal-Pro-Pro-Val-Phe-NH 2 was dissolved in 80 ml of methanol. 0.4 g of 10% palladium / carbon was added under a nitrogen atmosphere and the reaction mixture was hydrogenated at room temperature for 4 hours. After addition of 6.22 mL (81.24 mmol) of 37% aqueous formaldehyde solution, hydrogenation was continued for 5 hours. Filtration and evaporation of the solvent gave 15.6 g of crude product. Further purification was performed by dissolving the peptide in water, adjusting the pH to 2 and extracting the aqueous phase three times with ethyl acetate. The aqueous phase was then adjusted to pH 8-9 and extracted four times with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate, filtered and evaporated to give 11.3 g of purified product as white powder. Compounds were characterized by high speed atom bombardment mass spectroscopy ([M + H] + = 797).
실시예 2A: N,N-디메틸-Val-Val-NMe-Val-Pro-{1-[티아졸-(2)-일]-2-페닐}-에틸아미드Example 2A: N, N-dimethyl-Val-Val-NMe-Val-Pro- {1- [thiazol- (2) -yl] -2-phenyl} -ethylamide
배치 크기 3mmol에 상응하는, Fmoc-Pro-p-알콕시벤질-알코올-수지 4.11g (치환율: 0.73mmol/g)을 개개의 하기 물질 4.5mmol과 과정 Ib에서와 같이 반응시켰다:4.11 g of Fmoc-Pro-p-alkoxybenzyl-alcohol-resin (substitution rate: 0.73 mmol / g), corresponding to a batch size of 3 mmol, were reacted with 4.5 mmol of the following material as in process Ib:
Fmoc-N-MeVal-OHFmoc-N-MeVal-OH
Fmoc-Val-OHFmoc-Val-OH
Fmoc-Val-OHFmoc-Val-OH
N-메틸아미노산 다음에 위치하는 아미노산을 이 경우에 반응 시간을 늘리면서 PyBrop 또는 Bop-C1을 사용하여 이중 결합과 반응시켰다. 합성이 완결된 후, 펩티드-수지를 N 말단 탈보호시키고 (과정 Ib의 단계 2 내지 4), 과정 II에서와 같이 포름알데히드 수용액과 추가 반응시킨 후, 감압하에 건조시켰다. 이러한 방식으로 수득된 수지를 과정 IV에서와 같이 TFA 분해로 처리하였다. 미정제 생성물 (750㎎)을 후속 결합을 위해 직접 사용하였다. 이 화합물 100㎎을 실온에서 2일간 (S)-2-[1-아미노-2-페닐에틸]티아졸 45㎎ 및 PyBop 230㎎와 반응시키면서 DMF 중의 DIPEA 192㎕를 첨가하였다. 반응 혼합물을 겔 크로마토그래피 (SEPHADEX LH-20, 메탄올)에 의해 정제시키고, 생성물 분획을 조합하였다. 생성물 83㎎을 수득하였다.The amino acid located after the N-methylamino acid was reacted with the double bond using PyBrop or Bop-C1 in this case with increasing reaction time. After completion of the synthesis, the peptide-resin was N-terminal deprotected (steps 2-4 of Process Ib), further reacted with aqueous formaldehyde solution as in Process II, and then dried under reduced pressure. The resin obtained in this manner was treated by TFA decomposition as in process IV. Crude product (750 mg) was used directly for subsequent binding. 192 μl of DIPEA in DMF were added while reacting 100 mg of this compound with 45 mg of (S) -2- [1-amino-2-phenylethyl] thiazole and 230 mg of PyBop for 2 days at room temperature. The reaction mixture was purified by gel chromatography (SEPHADEX LH-20, methanol) and the product fractions combined. 83 mg of product was obtained.
실시예 1BExample 1B
Me2Val-Val-MeVal-Pro-Pro-NHCH(CH3)2 Me 2 Val-Val-MeVal-Pro-Pro-NHCH (CH 3 ) 2
a) Z-MeVal-Pro-OMea) Z-MeVal-Pro-OMe
Z-MeVal-OH 66.25g (250mmol)을 무수 디클로로메탄 250㎖에 용해시켰다. 트리에틸아민 36.41㎖ (262.5mmol)을 첨가시킨 후, 반응 혼합물을 -25℃로 냉각시키고, 피발로일 클로라이드 32.27㎖ (262.5mmol)을 첨가시켰다. 2.5시간 동안 교반시킨 후, 0℃에서 트리에틸아민 36.41㎖ (265.5mmol)로 중화된, 디클로로메탄 250㎖ 중의 H-Pro-OMe x HCl 41.89g (250mmol)을 반응 혼합물에 첨가하였다. 교반을 -25℃에서 2시간 동안 계속 수행하고, 실온에서 밤새 수행하였다. 반응 혼합물을 디클로로메탄으로 희석시키고, NaHCO3포화 수용액 (3X), 물 (1X), 5% 시트르산 (3X) 및 NaCl 포화 수용액으로 철저히 세척시켰다. 유기상을 황산나트륨으로 건조시키고, 여과시키고, 증발 건조시켰다. 잔류물 (91.24g)을 석유 에테르와 밤새 교반시키고, 여과시켰다. 생성물 62.3g을 수득하였다.66.25 g (250 mmol) of Z-MeVal-OH was dissolved in 250 mL of anhydrous dichloromethane. After addition of 36.41 mL (262.5 mmol) of triethylamine, the reaction mixture was cooled to -25 ° C and 32.27 mL (262.5 mmol) pivaloyl chloride were added. After stirring for 2.5 hours, 41.89 g (250 mmol) of H-Pro-OMe x HCl in 250 mL of dichloromethane, neutralized with 36.41 mL (265.5 mmol) of triethylamine at 0 ° C., were added to the reaction mixture. Stirring was continued for 2 h at −25 ° C. and overnight at rt. The reaction mixture was diluted with dichloromethane and washed thoroughly with saturated aqueous NaHCO 3 ( 3 ×), water (1 ×), 5% citric acid (3 ×) and saturated aqueous NaCl solution. The organic phase was dried over sodium sulphate, filtered and evaporated to dryness. The residue (91.24 g) was stirred with petroleum ether overnight and filtered. 62.3 g of product was obtained.
b) H-MeVal-Pro-OMeb) H-MeVal-Pro-OMe
Z-MeVal-Pro-OMe 48.9g (130mmol)을 메탄올 490㎖에 용해시켰다. 농축 염산 10.9㎖ (130mmol) 및 10% 팔라듐/숯 2.43g을 첨가시킨 후, 반응 혼합물을 수소화시켰다. 여과 및 증발 건조시켜서, 생성물 36.43g을 수득하였다.48.9 g (130 mmol) of Z-MeVal-Pro-OMe was dissolved in 490 mL of methanol. After addition of 10.9 mL (130 mmol) of concentrated hydrochloric acid and 2.43 g of 10% palladium / charcoal, the reaction mixture was hydrogenated. Filtration and evaporation to dryness yielded 36.43 g of product.
c) Z-Val-MeVal-Pro-OMec) Z-Val-MeVal-Pro-OMe
H-MeVal-Pro-OMe 18.1g (65mmol), Z-Val-N-카르복시무수물 21.6g (78mmol) 및 디이소프로필에틸아민 22.8㎖ (130mmol)을 40℃에서 2일간 DMF 110㎖ 중에서 교반시켰다. DMF를 증발시킨 후, 디크롤로메탄을 첨가시키고, 유기상을 NaHCO3포화 수용액 (3X), 물 (1X), 5% 시트르산 (3X) 및 NaCl 포화 수용액으로 세척시켰다. 유기상을 황산나트륨으로 건조시키고, 증발 건조시켰다. 생성물 (29.3g)을 점성 오일로서 수득하였다.18.1 g (65 mmol) of H-MeVal-Pro-OMe, 21.6 g (78 mmol) of Z-Val-N-carboxy anhydride and 22.8 mL (130 mmol) of diisopropylethylamine were stirred in 110 mL of DMF at 40 ° C. for 2 days. After evaporating DMF, dichloromethane was added and the organic phase was washed with saturated aqueous NaHCO 3 ( 3 ×), water (1 ×), 5% citric acid (3 ×) and saturated aqueous NaCl solution. The organic phase was dried over sodium sulfate and evaporated to dryness. Product (29.3 g) was obtained as a viscous oil.
d) H-Val-MeVal-Pro-OMed) H-Val-MeVal-Pro-OMe
Z-Val-MeVal-Pro-OMe 29.3g (61.6mmol)을 메탄올 230㎖에 용해시켰다. 10% 팔라듐/숯 1.15g을 첨가시킨 후, 반응 혼합물을 수소화시켰다. 여과 및 증발 건조시켜서, 생성물 21.96g을 수득하였다.29.3 g (61.6 mmol) of Z-Val-MeVal-Pro-OMe were dissolved in 230 mL of methanol. After addition of 1.15 g of 10% palladium / charcoal, the reaction mixture was hydrogenated. Filtration and evaporation to dryness yielded 21.96 g of product.
e) Z-Val-Val-MeVal-Pro-OMee) Z-Val-Val-MeVal-Pro-OMe
Z-Val-OH 15.29g (61mmol) 및 H-Val-MeVal-Pro-OMe 21.96g (61mmol)을 디크롤로메탄 610㎖에 용해시키고, 0℃로 냉각시켰다. N-메틸모르폴린 8.16㎖ (73.2mmol), HOBt 2.77g (20.3mmol) 및 EDCI 11.74g (61mmol)을 첨가시킨 후, 반응 혼합물을 실온에서 밤새 교반시키고, 디클로로메탄으로 희석시키고, NaHCO3포화 수용액 (3X), 물 (1X), 5% 시트르산 (3X) 및 NaCl 포화 수용액으로 철저히 세척시켰다. 유기상을 황산나트륨으로 건조시키고, 여과시키고, 증발 건조시켜서, 생성물 31.96g을 수득하였다.15.29 g (61 mmol) of Z-Val-OH and 21.96 g (61 mmol) of H-Val-MeVal-Pro-OMe were dissolved in 610 mL of dichloromethane and cooled to 0 ° C. After addition of 8.16 mL (73.2 mmol) of N-methylmorpholine, 2.77 g (20.3 mmol) of HOBt and 11.74 g (61 mmol) of EDCI, the reaction mixture was stirred overnight at room temperature, diluted with dichloromethane and saturated aqueous NaHCO 3 solution. (3X), water (1X), 5% citric acid (3X) and saturated aqueous NaCl solution were washed thoroughly. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness to afford 31.96 g of product.
f) Z-Val-Val-MeVal-Pro-OHf) Z-Val-Val-MeVal-Pro-OH
Z-Val-Val-MeVal-Pro-OMe 31.96g (57mmol)을 메탄올 250㎖에 용해시켰다. 1N LiOH 용액 102.6㎖을 첨가시키고, 혼합물을 실온에서 밤새 교반시켰다. 물 500㎖를 첨가시킨 후, 수성상을 에틸 아세테이트로 3회 세척시키고, 0℃에서 pH를 2로 조정시키고, 에틸 아세테이트로 3회 추출시켰다. 유기상을 황산나트륨으로 건조시키고, 여과시키고, 증발 건조시켜서, 원하는 생성물 30.62g을 백색 고체로서 수득하였다.31.96 g (57 mmol) of Z-Val-Val-MeVal-Pro-OMe was dissolved in 250 ml of methanol. 102.6 mL of 1N LiOH solution was added and the mixture was stirred at rt overnight. After addition of 500 ml of water, the aqueous phase was washed three times with ethyl acetate, the pH was adjusted to 2 at 0 ° C. and extracted three times with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness to afford 30.62 g of the desired product as a white solid.
g) Z-Val-Val-MeVal-Pro-Pro-NHCH(CH3)2 g) Z-Val-Val-MeVal-Pro-Pro-NHCH (CH 3 ) 2
Z-Val-Val-MeVal-Pro-OH 2g (3.35mmol) 및 H-Pro-NHCH(CH3)20.664g (3.35mmol)을 무수 디클로로메탄 34㎖에 용해시켰다. 0℃로 냉각시킨 후, N-메틸모르폴린 1.35㎖ (12.1mmol), HOBt 0.114g (0.84mmol) 및 EDCI 0.645g (3.35mmol)을 첨가시키고, 반응 혼합물을 실온에서 밤새 교반시켰다. 디클로로메탄 80㎖를 첨가시키고, 유기상을 NaHCO3포화 수용액 (3X), 물 (1X), 5% 시트르산 (3X) 및 NaCl 포화 수용액으로 철저히 세척시켰다. 유기상을 황산나트륨으로 건조시키고, 여과시키고, 증발 건조시켜서, 생성물 1.96g을 수득한 후, 이것을 추가 정제 없이 후속 반응에 사용하였다.2 g (3.35 mmol) of Z-Val-Val-MeVal-Pro-OH and 0.664 g (3.35 mmol) of H-Pro-NHCH (CH 3 ) 2 were dissolved in 34 mL of anhydrous dichloromethane. After cooling to 0 ° C., 1.35 mL (12.1 mmol) N-methylmorpholine, 0.114 g (0.84 mmol) HOBt and 0.645 g (3.35 mmol) EDCI were added and the reaction mixture was stirred at rt overnight. 80 ml of dichloromethane were added and the organic phase was washed thoroughly with saturated aqueous NaHCO 3 ( 3 ×), water (1 ×), 5% citric acid (3 ×) and saturated aqueous NaCl solution. The organic phase was dried over sodium sulphate, filtered and evaporated to dryness to afford 1.96 g of product which was used for the next reaction without further purification.
h) Me2Val-Val-MeVal-Pro-Pro-NHCH(CH3)2 h) Me 2 Val-Val-MeVal-Pro-Pro-NHCH (CH 3 ) 2
Z-Val-Val-MeVal-Pro-Pro-NHCH(CH3)21.96g을 메탄올 11㎖에 용해시켰다. 10% Pd/C 0.054g을 질소 분위기하에 첨가시키고, 반응 혼합물을 실온에서 4시간 동안 수소화시켰다. 37% 포름알데히드 수용액 0.86㎖ (11.24mmol) 및 10% Pd/C 0.281g을 첨가시킨 후, 수소화를 5시간 동안 계속 수행하였다. 용매를 여과 및 증발시켜서, 미정제 생성물 2.77g을 수득하였다. 펩티드를 물로 용해시키고, pH를 2로 조정시키고, 수성상을 에틸 아세테이트로 3회 추출함으로써 추가 정제를 수행하였다. 그 후, 수성상을 pH 8 내지 9로 조정시키고, 디클로로메탄으로 4회 추출하였다. 유기상을 황산나트륨으로 건조시키고, 여과시키고, 증발시켜서, 정제된 생성물 1.37g을 백색 포움으로서 수득하였다. 화합물을 중압 액체 크로마토그래피 를 사용하여 추가 정제시켰다 (10-50% A in 10min.; 50-90% A in 320min.). 생성물을 함유하는 단편을 조합시키고, 동결건조시키고, 물에 재용해시키고, 1N LiOH를 사용하여 pH를 9로 조정하였다. 디클로로메탄으로 추출한 후, 유기상을 황산나트륨으로 건조시키고, 여과시키고, 증발 건조시켰다. 동결건조에 의해 순 생성물 500㎎이 유도되며, 이것은 고속 충격 질량 분광학에 의해 특징화되었다 ([M+H]*= 593).1.96 g of Z-Val-Val-MeVal-Pro-Pro-NHCH (CH 3 ) 2 was dissolved in 11 ml of methanol. 0.054 g of 10% Pd / C was added under nitrogen atmosphere and the reaction mixture was hydrogenated at room temperature for 4 hours. After addition of 0.86 mL (11.24 mmol) of 37% aqueous formaldehyde solution and 0.281 g of 10% Pd / C, hydrogenation was continued for 5 hours. Filtration and evaporation of the solvent gave 2.77 g of crude product. Further purification was performed by dissolving the peptide with water, adjusting the pH to 2 and extracting the aqueous phase three times with ethyl acetate. The aqueous phase was then adjusted to pH 8-9 and extracted four times with dichloromethane. The organic phase was dried over sodium sulfate, filtered and evaporated to afford 1.37 g of purified product as white foam. The compound was further purified using medium pressure liquid chromatography (10-50% A in 10 min .; 50-90% A in 320 min.). Fragments containing the product were combined, lyophilized, redissolved in water, and the pH was adjusted to 9 with 1N LiOH. After extraction with dichloromethane, the organic phase is dried over sodium sulfate, filtered and evaporated to dryness. Lyophilization induced 500 mg of net product, which was characterized by high-speed impact mass spectroscopy ([M + H] * = 593).
실시예 2BExample 2B
Me2Val-Val-MeVal-Pro-Pro-NHC(CH3)3 Me 2 Val-Val-MeVal-Pro-Pro-NHC (CH 3 ) 3
a) Z-Val-Val-MeVal-Pro-Pro-NHC(CH3)3 a) Z-Val-Val-MeVal-Pro-Pro-NHC (CH 3 ) 3
Z-Val-Val-MeVal-Pro-OH 2g (3.35mmol) 및 H-Pro-NHC(CH3)30.692g (3.35mmol)을 무수 디클로로메탄 34㎖에 용해시켰다. 0℃로 냉각시킨 후, N-메틸모르폴린 1.35㎖ (12.1mmol), HOBt 0.114g (0.84mmol) 및 EDCI 0.645g (3.35mmol)을 첨가시키고, 반응 혼합물을 실온에서 밤새 교반시켰다. 디클로로메탄 80㎖를 첨가시키고, 유기상을 NaHCO3포화 수용액 (3X), 물 (1X), 5% 시트르산 (3X) 및 NaCl 포화 용액으로 철저히 세척시켰다. 유기상을 황산나트륨으로 건조시키고, 여과시키고, 증발 건조시켜서, 생성물 1.8g을 수득한 후, 이것을 추가 정제 없이 후속 반응에서 사용하였다.2 g (3.35 mmol) of Z-Val-Val-MeVal-Pro-OH and 0.692 g (3.35 mmol) of H-Pro-NHC (CH 3 ) 3 were dissolved in 34 mL of anhydrous dichloromethane. After cooling to 0 ° C., 1.35 mL (12.1 mmol) N-methylmorpholine, 0.114 g (0.84 mmol) HOBt and 0.645 g (3.35 mmol) EDCI were added and the reaction mixture was stirred at rt overnight. 80 ml of dichloromethane were added and the organic phase was washed thoroughly with saturated aqueous NaHCO 3 ( 3 ×), water (1 ×), 5% citric acid (3 ×) and saturated NaCl. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness to yield 1.8 g of product which was used in the next reaction without further purification.
b) Me2Val-Val-MeVal-Pro-Pro-NHC(CH3)3 b) Me 2 Val-Val-MeVal-Pro-Pro-NHC (CH 3 ) 3
Z-Val-Val-MeVal-Pro-Pro-NHC(CH3)31.8g을 메탄올 10㎖에 용해시켰다. 10% Pd/C 0.045g을 질소 분위기하에 첨가시키고, 반응 혼합물을 실온에서 4시간 동안 수소화시켰다. 37% 포름알데히드 수용액 0.86㎖ (11.24mmol) 및 10% Pd/C 0.252g을 첨가시킨 후, 수소화를 5시간 동안 계속 수행하였다. 용매를 여과 및 증발시켜서, 미정제 생성물 1.82g을 수득하였다. 화합물을 중압 액체 크로마토그래피를 사용하여 추가 정제시켰다 (10-50% A in 10min.; 50-90% A in 320min.). 생성물을 함유하는 단편을 조합시키고, 동결건조시키고, 물에 재용해시키고, 1N LiOH를 사용하여 pH를 9로 조정하였다. 디클로로메탄으로 추출한 후, 유기상을 황산나트륨으로 건조시키고, 증발 건조시켰다. 동결건조에 의해 순 생성물 547㎎이 유도되며, 이것은 고속 원자 충격 질량 분광학에 의해 특징화되었다 ([M+H]*= 607).1.8 g of Z-Val-Val-MeVal-Pro-Pro-NHC (CH 3 ) 3 was dissolved in 10 ml of methanol. 0.045 g of 10% Pd / C was added under nitrogen atmosphere and the reaction mixture was hydrogenated at room temperature for 4 hours. After addition of 0.86 mL (11.24 mmol) of 37% aqueous formaldehyde solution and 0.252 g of 10% Pd / C, hydrogenation was continued for 5 hours. Filtration and evaporation of the solvent gave 1.82 g of crude product. The compound was further purified using medium pressure liquid chromatography (10-50% A in 10 min .; 50-90% A in 320 min.). Fragments containing the product were combined, lyophilized, redissolved in water, and the pH was adjusted to 9 with 1N LiOH. After extraction with dichloromethane, the organic phase is dried over sodium sulfate and evaporated to dryness. Lyophilization induced 547 mg of net product, which was characterized by high speed atomic impact mass spectroscopy ([M + H] * = 607).
생물학적 활성의 평가Assessment of Biological Activity
생체내 방법In vivo method
화학식 (I)의 화합물과 파클리택셀, 택소테레 또는 개질된 택산 또는 택소이드 유사체의 조합물은 임상적 효용을 암시하는 생체내 활성에 대한 다수의 임상전 검정으로 추가 시험하였다. P388 (복수 모델), LX-1, CX-1 및 PC-3 (폐, 결장 및 전립성에 대한 사람 종양 이종이식편 모델) 종양 모델은 모두 본 발명에 사용하기에 적당하다.Combinations of compounds of formula (I) with paclitaxel, taxotere or modified taxanes or taxoid analogs were further tested in a number of preclinical assays for in vivo activity suggestive of clinical utility. P388 (plural models), LX-1, CX-1 and PC-3 (human tumor xenograft models for lung, colon and prostate) Tumor models are all suitable for use in the present invention.
일반적으로, 두 작용제 모두에 대해 허용 수준의 항종양 활성을 제공하는 것으로 여겨지는 임의의 투여 방법이 적당하다. 임의의 허용되는 약제 투여 방법은 본 발명의 조합 치료법에서 이용될 수 있으며, 당업자에게 잘 알려진 기법을 사용하여 결정될 수 있다. 또한, 약제는 임의의 순서로, 동시 또는 순차 투여될 수 있다.In general, any method of administration that is believed to provide acceptable levels of antitumor activity for both agents is suitable. Any acceptable method of administering the medicament may be used in the combination therapy of the present invention and may be determined using techniques well known to those skilled in the art. In addition, the agents may be administered in any order, simultaneously or sequentially.
P388 MODELP388 MODEL
P388 종양 모델은 쥐과동물 림프구 백혈병 세포계 (참조: Schabel et al., Pharmac. Ther. A, 1:411-435)를 사용한다. 본 발명에 사용된 P388 종양 세포를, 공여체 마우스로부터 이식후 7일째에 복강 세척에 의해 수거하였다. 그 후, P388 종양 세포 1x106개를 0.5㎖ 부피로 마우스에 복강내 주입하였다.The P388 tumor model uses a murine lymphocytic leukemia cell line (Schabel et al., Pharmac. Ther. A, 1: 411-435). P388 tumor cells used in the present invention were harvested by intraperitoneal washing 7 days after transplantation from donor mice. Thereafter, 1 × 10 6 P388 tumor cells were injected intraperitoneally in mice at a volume of 0.5 ml.
전형적인 투여 방법은 이식후 약 1일째 치료를 개시한 후, 이식후 5일 및 9일째 치료하는 것을 포함한다. 일반적으로, 화학식 (I)의 화합물은 정맥내(i.v.) 투여되고, 파클리택셀, 택소테레 또는 개질된 택산 또는 택소이드 유사체는 복강내(i.p.) 투여된다.Typical methods of administration include initiating treatment about 1 day after transplantation followed by treatment on days 5 and 9 after transplantation. Generally, compounds of formula (I) are administered intravenously (i.v.) and paclitaxel, taxotere or modified taxanes or taxoid analogs are administered intraperitoneally (i.p.).
P388 세포에 대한 본 발명의 조합물의 치료 결과는 치료된 (T) 군 대 대조 (C) 군의 상대적 평균 수명(MST)에 의해 반영되는 수명의 증가로 나타나며 (비치료된 마우스의 생존 기간은 일반적으로 11 내지 13일임), %T/C 값으로 표현된다. 국립 암 협회 지침에 따르면, 128 내지 190%의 %T/C는 중간 내지 양호한 활성을 갖는 약제를 나타낸다. 또한, 순 로그 세포치사율 (Net log Cell Kill)은 상이한 스케줄 및 조합물의 효능을 비교하기 위해 사용되며, 하기 식와 같이 계산된다:The result of treatment of the combination of the present invention on P388 cells results in an increase in lifespan reflected by the relative mean lifespan (MST) of the treated (T) vs. the control (C) group (survival of untreated mice is generally 11 to 13 days), expressed as a% T / C value. According to the National Cancer Society guidelines, 128% to 190% of% T / C represent drugs with moderate to good activity. In addition, Net log Cell Kill is used to compare the efficacy of different schedules and combinations and is calculated as follows:
순 로그 세포치사율 = [T-C) - 치료 기간] x 0.332Net log cell death rate = [T-C)-duration of treatment] x 0.332
배증 시간Doubling time
상기 식에서,Where
배증 시간은 대조표준 종양이 1회 배증하는 데 필요한 시간 (0.4일)이고,The doubling time is the time required for one doubling of the control tumor (0.4 days),
T 및 C는 대조표준 (C) 및 치료된 (T) 마우스에 대한 평균 수명 (일)이고,T and C are mean lifespan (days) for control (C) and treated (T) mice,
약제에 의한 치료 기간이고,The duration of treatment with the drug,
0.332는 유도 상수이다.0.332 is the induction constant.
순 로그 세포치사율이 플러스이면 치료 말기에 종양 세포가 거의 존재하지 않음을 나타낸다. 마이너스이면 종양이 치료 동안에 여전히 증식하고 있음을 나타낸다.Positive net log cell mortality indicates little tumor cells at the end of treatment. Negative indicates that the tumor is still growing during treatment.
실시예 3: P388 종양 모델에 대한 화합물 (xvii)과 파클리택셀을 사용한 조합 치료Example 3: Combination Treatment with Compound (xvii) and Paclitaxel for P388 Tumor Model
P388 종양 세포 1 x 106개를 0.5㎖의 부피로 마우스에 복강내 이식시켰다. 치료를 1일 후에 개시한 후, 이식후 5일 및 9일째에 치료하였다. 화합물 (xvii)를 정맥내 투여하고, 파클리택셀을 복강내 투여하였다. 화합물 (xvii)를 20, 40 또는 60㎎/㎏으로 투여하고, 파클리택셀을 10, 20 또는 30㎎/㎏으로 투여하였다. 투여는 화합물 (xvii)을 먼저 투여한 후, 1시간 뒤에 파클리택셀을 투여하는 순차 투여였다.1 × 10 6 P388 tumor cells were implanted intraperitoneally in mice at a volume of 0.5 ml. Treatment was initiated 1 day later and then treated 5 and 9 days after transplantation. Compound (xvii) was administered intravenously and paclitaxel was administered intraperitoneally. Compound (xvii) was administered at 20, 40 or 60 mg / kg and paclitaxel was administered at 10, 20 or 30 mg / kg. Administration was sequential administration of compound (xvii) first followed by paclitaxel 1 hour later.
결과:result:
실시예 3으로부터의 결과를 표 1에 나타내었다. 표 1에 기재된 데이터는 1회 약제 치료에 의해, 60㎎/㎏ 용량으로 정맥 투여되는 경우에 순 로그 세포치사율 (NlCK) 0.66에 상응하는 화합물 (xvii)에 대한 최적 %T/C 175%가 초래되고, 10㎎/㎏ 용량으로 복강내 투여되는 경우에 파클리택셀에 대해 NICK 1.33에 상응하는 최적 %T/C 183%가 초래된다는 것을 나타낸다. 조합 약제 치료의 경우, 표 1의 데이터는 60㎎/㎏ (xvii) 및 파클리택셀 20㎎/㎏이 조합되면 수명의 현저한 증가 (만휘트니(MannWhitney) 시험에 의해 결정하여, 0.001 미만의 P 값) 및 60일 넘게 생존하는 동물의 38%에 대해 NICK 5.98에 상응하는 242%의 최적 %T/C 값이 초래됨을 나타낸다.The results from Example 3 are shown in Table 1. The data shown in Table 1 resulted in an optimal% T / C 175% for compound (xvii) corresponding to net log cell death rate (NlCK) 0.66 when administered intravenously at a 60 mg / kg dose by a single drug treatment. And intraperitoneal administration at a 10 mg / kg dose results in an optimal% T / C 183% corresponding to NICK 1.33 for paclitaxel. For combination drug treatment, the data in Table 1 show a significant increase in lifespan when 60 mg / kg (xvii) and paclitaxel 20 mg / kg are combined (P value less than 0.001, as determined by the MannWhitney test). ) And an optimal% T / C value of 242% corresponding to NICK 5.98 for 38% of animals surviving over 60 days.
사람 종양 이종이식편 모델Human Tumor Xenograft Model
무흉선 누드 마우스에서 증식시킨 폐 (LX-1), 결장 (CX-1) 및 전립선 (PC-3)으로부터의 사람 종양을, 당 분야에 널리 알려진 바와 같이, 새로운 수용체 마우스에 이식시켰다. 이식된 종양 단편은 크기가 약 50㎎ 이었다. 이식한 일을 0일째로 지정하였다. 본 발명의 조합 치료법을, 이종이식편 함유 마우스에 투여한 후 항종양 효능에 대해 평가하였다.Human tumors from lung (LX-1), colon (CX-1) and prostate (PC-3) grown in athymic nude mice were transplanted into new receptor mice, as is well known in the art. The transplanted tumor fragment was about 50 mg in size. The transplant day was designated as day 0. The combination therapy of the present invention was evaluated for antitumor efficacy after administration to xenograft containing mice.
조합 치료법을 두 약제 모두를 정맥 투여함으로써 달성하였다. Q2dx3; 5, 12 및 19 주사 스케줄을, 화합물 (xvii)을 투여한 지 1시간 후에 투여되는 파클리택셀로 수행하였다. 바꿔 말하면, 치료를 종양 이식 후, 5일, 12일 및 19일째에 개시되는 3가지 사이클로 구성하였다. 치료의 한 사이클을 전체 3회에 대해 하루 걸른 치료로 구성하였다. 시험된 사람 이종이식편 모델의 LX-1 및 CX-1에 사용되는 화합물 (xvii) 및 파클리택셀 둘 모두의 1회 투여에 대한 최적 용량은 표 2 및 3에서 발견될 수 있고, PC-3 모델에 대해서는 최적 용량이 결정되지 않았다.Combination therapy was achieved by intravenous administration of both agents. Q2dx3; 5, 12 and 19 injection schedules were performed with paclitaxel administered 1 hour after administration of Compound (xvii). In other words, treatment consisted of three cycles that began 5, 12 and 19 days after tumor transplantation. One cycle of treatment consisted of one day of treatment for all three. Optimal doses for single administration of both compound (xvii) and paclitaxel used in LX-1 and CX-1 of the tested human xenograft model can be found in Tables 2 and 3, PC-3 model No optimal dose was determined for.
종양 직경 및 체중을 일주일에 2회 측정하였다. 종양 부피를 버어니어 캘리퍼스로 측정된 직경 및 하기 식을 이용하여 계산하였다:Tumor diameter and body weight were measured twice a week. Tumor volume was calculated using the diameter measured with vernier calipers and the following formula:
(길이 x 폭2) / 2 = 종양 중량 (mg)(Length x width 2 ) / 2 = tumor weight (mg)
평균 종양 중량 (MTW)을 각각의 치료 군에 대해 계산하고, 비치료된 대조표준의 종양에 대한 각각의 군에 대한 T/C 값을 결정하였다.Mean tumor weight (MTW) was calculated for each treatment group and T / C values for each group for tumors of the untreated control were determined.
결과를 또한 순 로그 세포치사율로서 나타내고, 하기 식과 같이 계산하였다:The results are also expressed as net log cell mortality and calculated as follows:
순 로그 세포치사율 = [T-C) - 치료 기간] x 0.332Net log cell death rate = [T-C)-duration of treatment] x 0.332
배증 시간Doubling time
T와 C는 대조군 및 치료된 군의 종양이 특정 종양 크기, 이 경우에는 2000mm에 도달하는 데에 필요한 평균 일수를 나타낸다.T and C represent the average days required for tumors in the control and treated groups to reach a particular tumor size, in this case 2000 mm.
배증 시간은 대조표준 종양이 1회 배증하는 데 필요한 시간 (0.4일)이다.The doubling time is the time (0.4 days) required for a single doubling of the control tumor.
0.332는 유도 상수이다.0.332 is the induction constant.
실시예 4: LX-1 사람 종양 이종이식편 모델에 대해 LX-1 사람 종양 이종이식편 모델에 대해 화합물 103793 및 파클리택셀을 사용하는 조합 치료법Example 4 Combination Therapies Using Compound 103793 and Paclitaxel for LX-1 Human Tumor Xenograft Model
Q2dx3; 전술된 5, 12 및 19 투여 방법을 이 실시예에서 사용하였다. 화합물 (xvii)을 정맥내 투여한 지 1시간 후, 파클리택셀을 정맥내 투여하였다. 파클리택셀 및 화합물 (xvii) 둘 모두의 최적 1회 용량은 표 2로부터 결정될 수 있다.Q2dx3; The aforementioned 5, 12 and 19 dosing methods were used in this example. 1 hour after intravenous administration of compound (xvii), paclitaxel was administered intravenously. The optimal single dose of both paclitaxel and compound (xvii) can be determined from Table 2.
표 1Table 1
P388 생체내 종양 모델에 대한, 파클리택셀의 존재 및 부재하의 화합물 (xvii)의 용량 반응Dose response of compound (xvii) with and without paclitaxel to P388 in vivo tumor model
Q4Dx3; (xvii) 주사 한지 1시간 후 1 파클리택셀이 주사됨Q4Dx3; (xvii) 1 paclitaxel is injected 1 hour after injection
실시예 5: CX-1 사람 종양 이종이식편 모델에 대한 화합물 103793과 파클리택셀을 사용한 조합 치료법Example 5: Combination Therapy with Compound 103793 and Paclitaxel on CX-1 Human Tumor Xenograft Model
Q2dx3; 전술된 5, 12 및 19 투여 방법을 이 실시예에서 사용하였다. 화합물 (xvii)을 정맥내 투여한 지 1시간 후 파클리택셀을 정맥내 투여하였다. 파클리택셀 및 화합물 (xvii) 둘 모두에 대한 최적 1회 용량은 표 3으로부터 결정될 수 있다.Q2dx3; The aforementioned 5, 12 and 19 dosing methods were used in this example. Paclitaxel was administered intravenously 1 hour after intravenous administration of compound (xvii). The optimal single dose for both paclitaxel and compound (xvii) can be determined from Table 3.
실시예 6: CX-1 사람 종양 이종이식편에 대한 화합물 103793과 파클리택셀을 사용한 조합 치료법Example 6: Combination Therapy with Compound 103793 and Paclitaxel for CX-1 Human Tumor Xenografts
Q2dx3; 전술된 5, 12 및 19 투여 방법을 이 실시예에 사용하였다. 화합물 (xvii)를 정맥내 투여한 지 한 시간 후에 파클리택셀을 복강내 투여하였다. 파클리택셀 및 화합물 (xvii) 둘 모두에 대한 최적 1회 용량은 결정되지 않았다.Q2dx3; The 5, 12 and 19 dosing methods described above were used in this example. Paclitaxel was administered intraperitoneally one hour after intravenous administration of compound (xvii). The optimal single dose for both paclitaxel and compound (xvii) was not determined.
결과:result:
본 발명의 조합 치료법의 항종양 효능을 평가하기 위해 사람 이종이식편 모델을 사용하여 수득한 결과를 표 2 내지 4에 나타내었다. 제시된 데이터는 예비 실험으로부터의 결과를 나타낸다. 표 2에 있는 데이터는 LX-1 모델에 대해, 화합물 (xvii) 및 파클리택셀의 최적 조합은 각각 15㎎/㎏ 및 10㎎/㎏임을 나타낸다. 조합에 의해 약간의 퇴행 및 종양 성장 지연이 유도되었다. 그러나, CX-1에 대한 동일한 조합 스케줄에 의해서는 표 3에 도시된 단일 약제 치료 보다 나은 임의의 잇점이 유도되지 않았다.The results obtained using the human xenograft model to assess antitumor efficacy of the combination therapy of the present invention are shown in Tables 2-4. The data presented represent the results from preliminary experiments. The data in Table 2 show that for the LX-1 model, the optimal combination of compound (xvii) and paclitaxel was 15 mg / kg and 10 mg / kg, respectively. The combination induced some regression and delayed tumor growth. However, the same combination schedule for CX-1 did not lead to any benefit over the single drug treatment shown in Table 3.
PC-3 모델의 경우, 단일 약제 치료와 비교하여 조합의 유리한 효과는 없었다. 그러나, 1회 투여에 대한 최적 용량은 결정되지 않았다.For the PC-3 model, there was no beneficial effect of the combination compared to single drug treatment. However, the optimal dose for a single dose has not been determined.
표 2TABLE 2
★Q2Dx3; 5,12,19 화합물 (xvii)가 주사된 지 1시간 후 파클리택셀이 주사됨 ★ Q2Dx3; Paclitaxel was injected 1 hour after injection of 5,12,19 compound (xvii)
표 3TABLE 3
★Q2Dx3; 5,12,19 화합물 (xvii)가 주사된 지 1시간 후 파클리택셀이 주사됨 ★ Q2Dx3; Paclitaxel was injected 1 hour after injection of 5,12,19 compound (xvii)
표 4Table 4
★Q2Dx3; 5,12,19 화합물 (xvii)가 주사된 지 1시간 후 파클리택셀이 주사됨 ★ Q2Dx3; Paclitaxel was injected 1 hour after injection of 5,12,19 compound (xvii)
하기 화합물은 실시예에 따라 제조되었고, 제조될 수 있다:The following compounds were prepared according to the examples and can be prepared:
합성된 신규한 화합물의 MS 특성에 대한 예를 하기 열거하였다:Examples of MS properties of the novel compounds synthesized are listed below:
화학식 (I)의 화합물의 설명에 사용된 부호는 하기 의미를 갖는다:The symbols used in the description of compounds of formula (I) have the following meanings:
Xaa: N,N-디메틸발린Xaa: N, N-dimethylvaline
Xab: N-메틸발린Xab: N-methylvaline
Xda: N-메틸-2-아미노부티로일Xda: N-methyl-2-aminobutyroyl
Xdb: 2-아미노부티로일Xdb: 2-aminobutyroyl
Xdc: N,N-디메틸-2-아미노부티로일Xdc: N, N-dimethyl-2-aminobutyroyl
Xdd: N,N-디메틸-2-3차부틸글리신Xdd: N, N-dimethyl-2-tert-butylglycine
Xde: N,N-디메틸-이소루신Xde: N, N-dimethyl-isoleucine
Xdf: 2-3차부틸글리신Xdf: 2-3 tertiary butyl glycine
Xer: N-메틸루신Xer: N-methylleucine
Xes: N-아세틸-N-메틸발린Xes: N-acetyl-N-methylvaline
Xet: 피페콜린산Xet: pipecolic acid
Xeu: N,N-디부틸발린Xeu: N, N-dibutylvaline
Xfk: N-에틸발린Xfk: N-ethylvaline
Xfl: N-메틸-3-3차부틸알라닌Xfl: N-methyl-3-tert-butylalanine
균등물Equivalent
당업자는 단지 일상적인 실험을 사용하여 본 발명의 특정 구체예에 대한 다수의 균등물을 인식하거나 확인할 수 있을 것이다. 이러한 균등물을 하기 특허청구의 범위에 포함시키고자 한다.Those skilled in the art will recognize, or be able to ascertain, many equivalents to certain embodiments of the invention using only routine experimentation. Such equivalents are intended to be included in the scope of the following claims.
Claims (36)
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US8/819,101 | 1997-03-13 | ||
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US20040101511A1 (en) * | 2000-11-08 | 2004-05-27 | Young Aiping H | Combination preparation of a biological response modifier and an anticancer agent and uses thereof |
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JP5841072B2 (en) | 2010-02-10 | 2016-01-06 | イミュノジェン・インコーポレーテッド | CD20 antibody and use thereof |
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WO2021246471A1 (en) * | 2020-06-03 | 2021-12-09 | 中外製薬株式会社 | Efficient peptide condensation method for difficult sequences |
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